Randomized, Controlled Trial of Dexamethasone in Neonatal Chronic Lung Disease: 13- to 17-Year Follow-up Study: II. Respiratory Status, Grow
http://www.100md.com
《小儿科》
the National Perinatal Epidemiology Unit, Oxford University, Oxford, United Kingdom
ABSTRACT
Objectives. To study the growth, health status, and respiratory outcomes at 13 to 17 years of infants enrolled in a double-blind, randomized, controlled trial of dexamethasone for the treatment of neonatal chronic lung disease.
Participants. A total of 287 infants who were chronically dependent on supplementary oxygen between 2 and 12 weeks of age were recruited from 31 centers in 6 countries to a double-blind, randomized, controlled trial of dexamethasone base (0.5 mg/kg per day for 1 week) or placebo, and survivors were evaluated at 3 years. Children from the 25 British and Irish centers were traced for reassessment at 13 to 17 years of age.
Outcome Measures. Respiratory symptoms, lung-function testing, height, weight, head circumference, blood pressure, health resource usage, and school absences.
Results. There was no significant difference in respiratory outcomes between the dexamethasone and placebo groups. Lung function was impaired but with no difference between the 2 groups. Growth was also impaired in both groups, with height z score of –0.7, weight z score of –0.4, and head circumference z score of –1.1. Systolic blood pressure was >95th percentile for age and height for 15% of children, but with no difference between the 2 groups. There was no difference in the numbers of hospital admissions for respiratory causes or other causes.
Conclusions. Despite a shorter duration of neonatal assisted ventilation, there is no evidence that dexamethasone use is associated with long-term improvement in lung function. Impaired growth and poor health status are long-term consequences of neonatal chronic lung disease, irrespective of exposure to neonatal dexamethasone.
Key Words: randomized controlled trial dexamethasone neonatal chronic lung disease follow-up respiratory lung function blood pressure health status growth
Abbreviations: CLD, chronic lung disease FVC, forced vital capacity FEV1, forced expiratory volume in 1 second RR, relative risk CI, confidence interval GP, general practitioner
Neonatal chronic lung disease (CLD) is a common complication of very low birth weight1 and is associated with continuing childhood ill health.2 Survivors assessed in later childhood3 and even into young adult life4,5 may show impaired lung function and also impaired growth. The benefits of prenatal steroid therapy in reducing rates of surfactant-deficient respiratory distress syndrome and improving survival rates are well established.6 Systematic reviews of a large number of randomized trials of steroids, especially dexamethasone, in the prevention or treatment of neonatal CLD have shown reduced duration of assisted ventilation and oxygen therapy.7–9
Theoretically, one might expect that early use of steroids to downregulate the inflammatory response and to decrease the duration of assisted ventilation would lead to earlier resolution of CLD and improved lung function at follow-up evaluations. However, concerns have been raised that steroids given during a phase of rapid lung growth and maturation could have harmful rather than beneficial long-term effects. Fetal rabbits given a single dose of corticosteroid showed impaired lung growth and cell division,10 although this effect disappeared by 1 month of age.11 Newborn rats given multiple doses of glucocorticoid showed changes in lung architecture that persisted into adult life.12 However, follow-up evaluations of infants randomized to receive corticosteroids, whether prenatally13 or postnatally,14 have not demonstrated any significant effect on later respiratory morbidity. A clear link has been shown between small lungs in infancy and subsequent wheezing.15 If somatic growth is impaired, then lung growth may also be affected. Neonatal steroid therapy has been associated with impaired somatic growth during treatment,16 even with short courses of treatment. In one follow-up study, steroid-treated boys were significantly shorter and lighter at 2 years of age than were their placebo-treated counterparts,17 and these same children were shorter and demonstrated smaller head circumference at 8 years of age.18 Others have not demonstrated any significant difference in subsequent growth.14 Systemic hypertension is a recognized complication of neonatal CLD,19 but information on blood pressure in later childhood is lacking. In several studies, neonatal steroid therapy was associated with an increase in blood pressure.7–9 Although this was usually mild, it is not known whether this increase was sustained at a later age.
This report from a large, randomized, controlled trial of neonatal dexamethasone therapy20 is the first to report on health status in adolescence, with particular regard to respiratory symptoms, lung function, blood pressure, and growth. The accompanying article reports on neurodevelopmental and educational status.21
METHODS
Participants
Between 1984 and 1989, 287 infants with neonatal CLD were recruited to an international, randomized, controlled trial of dexamethasone therapy.20 Infants were eligible if they had no major congenital malformations and were dependent on supplementary oxygen, with their condition being static or deteriorating, at 2 to 12 weeks of age (median age: 4 weeks). They were randomized through telephone contact with a central office, with stratification according to center and whether they were still receiving assisted ventilation (61%) or not (39%), to receive either dexamethasone base (0.5 mg/kg per day for 1 week) or placebo, given intravenously or orally and with the option of a second tapering 9-day course. Clinicians were allowed to prescribe open-label dexamethasone if there was life-threatening deterioration, but they remained blinded to the trial treatment allocation. Survivors were evaluated at 3 years of age.14 Children from the 25 British and Irish centers were traced for reassessment at 13 to 17 years of age21 and were contacted through their general practitioners (GPs). Assessments were conducted in the children's own homes between 2001 and 2002; study nurses and families remained blinded to the original treatment allocation.
Research Ethics Committee Approval
Approval for the present study was obtained from the Anglia and Oxford Multicenter Research Ethics Committee, and the appropriate local research ethics committees were informed. Informed consent from the children and their parents was obtained for each aspect of the study.
Assessment Tools
Lung-function testing was conducted with a standard electronic spirometer (Vitalograph Alpha III, Vitalograph Ltd, Buckingham, United Kingdom). The research nurses were all given training in spirometry by an experienced pediatric respiratory physiologist (Caroline Beardsmore). They conducted practice lung-function testing with volunteer children through local schools or pediatric departments, sending flow loops for review, until all 3 nurses were able to recognize satisfactory tracings reliably. Children were asked to avoid using -receptor agonist inhalers for 4 hours before their assessments, but use of steroid inhalers continued as normal. At each home visit, the spirometer was calibrated. Lung-function testing was performed according to the American Thoracic Society standardized protocol.22 Children were instructed and were then asked to perform a complete forced expiration and inspiration, with the child seated and wearing a nose clip. The test was repeated until 3 satisfactory loops had been obtained. The test was abandoned after a maximum of 8 attempts. Inhaled salbutamol (400 μg) was then administered with a spacer device, and the lung-function tests were repeated 15 minutes later. For children unfamiliar with the spacer device, initial practice was performed with a placebo. All flow loops were examined visually. Results were rejected if the 2 best forced vital capacity (FVC) measurements were not within 10% of each other (5% preferred). The best values for FVC and forced expiratory volume in 1 second (FEV1) were selected. The FEV1/FVC ratio was calculated with the best FEV1 and the best FVC. Forced expiratory flow in the middle 2 quartiles of expiration was taken from the loop with the greatest sum of FVC plus FEV1. Any flow-volume loops of questionable quality and a representative sample of all other loops were scrutinized by Caroline Beardsmore, who was blinded to the trial allocation, to ensure standard interpretation by the 3 study nurses. Results were converted into z scores by using published reference ranges for age and height.23,24 Weight was recorded with portable digital scales accurate to 0.1 kg. Height was measured with a Leicester portable height meter, and head circumference was measured with a standard paper tape. These measurements were converted into SD scores (z scores) for the child's age by using national normative data.25 Blood pressure was measured with a portable digital sphygmomanometer (Omron M4, Omron Healthcare [UK] Ltd, Milton Keynes, United Kingdom). Adult and pediatric cuffs were available, and the correct size was chosen. Blood pressure was measured in the right arm, with the child seated. Results were compared with normative data for age, height, and gender among adolescents.26
Health Questionnaires
A health questionnaire was completed by the families and by their GPs, ascertaining respiratory symptoms, other health problems or diagnoses, medications, and GP or hospital attendance. The respiratory symptom questions were taken from a standardized questionnaire.27 All questionnaires are available from the author or electronically (www.npeu.ox.ac.uk/dex).
Sample Size, Outcome Measures, and Statistical Methods
The sample size was predetermined by the size required for the original randomized trial minus any deaths and enrollments from centers outside Britain and Ireland. The primary outcome measures were the proportions of children >2 SD below the mean for FEV1 and for height. A sample size of 195 yielded an 80% chance of showing an increase in incidence in the primary outcomes from 20% to 39% or a decrease to 6%. Secondary respiratory outcome measures included z scores for all lung-function parameters, evidence of reversible airway disease (postsalbutamol FEV1 that was 80% of the predicted value and was increased by 10% over the baseline value), partially reversible airway disease (postsalbutamol FEV1 that was <80% of the predicted value despite an increase of 10% over the baseline value), or fixed airway disease (postsalbutamol FEV1 that was <80% of the predicted value with an increase of <10% over the baseline value), and frequency of respiratory symptoms, inhaler use, and hospital admissions. Other secondary outcome measures included weight, height, BMI, and head circumference z scores and systolic and diastolic blood pressure of >95th percentile and >50th percentile for age, gender, and height. Statistical analyses were performed on an intention-to-treat basis, with SPSS version 11 software (SPSS, Chicago, IL). Results are given as relative risks (RRs) or RR differences with 95% confidence intervals (CIs); the 2 test for trend was used.
RESULTS
Of 287 children recruited, 43 children were from North American or continental European centers not included in this study, consent for the original trial was refused for 3 children, and 46 children died before the 3-year follow-up assessment, leaving 195 eligible children. A total of 145 children (76%) completed a health questionnaire, and Fig 1 gives details of measurements completed. There was no evidence of any differences between the children included in the follow-up study and those not included, in particular with regard to open-label steroid usage.21
Results of lung-function testing are shown in Table 1. Although the majority of children had lung function falling within the normal range, z scores showed that both groups of children had results below those expected for age and height, but with no difference between the 2 groups. The health questionnaire revealed approximately one third of children with a diagnosis of asthma and 24% using antiasthma inhalers, but with no significant differences between the groups (Table 2). Growth and blood pressure measurements are shown in Table 3. The 2 groups of children showed similar reductions in weight, height, and head circumference, compared with normative data for their age. Systolic blood pressure was above the 97th percentile for 15% of children, but with no difference between the 2 groups. There was a high level of reported morbidity in the children, almost one half of whom were still receiving some specialist care (Table 4).
Use of open-label steroids for 39% of the placebo-treated children, compared with 11% of the dexamethasone-treated group, had the potential to reduce any differences between the 2 groups. A secondary analysis was performed for the primary outcome measures for the 2 groups, stratified according to centers' use of open-label steroids (Table 5). There were no significant differences in the risk of low FVC, low FEV1, or low height, or in the ratios of RRs in interaction tests, when children from centers with no, low, or high steroid usage were compared.
DISCUSSION
This study has monitored a group of infants with severe neonatal CLD and has confirmed that large proportions of these children have ongoing respiratory symptoms and impaired lung function in adolescence.4 Koumbourlis et al5 monitored preterm infants through childhood and showed that impaired lung function continued to improve into adolescence, but the authors did not report on steroid usage. Our patients showed reduced ventilator requirements and earlier extubation after neonatal dexamethasone usage.20 However, we have seen no demonstrable effect of sustained benefits for lung function. Conversely, this study showed no evidence that use of steroids in the neonatal period caused long-term lung damage, as suggested by animal studies.12 In particular, FVC was better preserved than FEV1, which would not be the case if alveolar size and numbers were diminished. Constraints on alveolar development are likely to be multifactorial; therefore, any adverse effect of dexamethasone may be small, compared with the adverse effects of preterm birth itself.
This study confirmed the long-term effects on growth associated with neonatal CLD,4 with survivors being shorter and lighter than expected for age. The mean head circumference in adolescence was 1 SD below expected, and this finding is reflected in the higher levels of neurodisability among these children.21 However, no differences in any growth parameters were seen between the dexamethasone group and the placebo group. Blood pressure was increased regardless of treatment allocation. Neonatal hypertension accompanying CLD has been reported to resolve during infancy.28 Hypertension in adult life is, however, an increasingly recognized complication of low birth weight itself.29
As discussed in the accompanying article, the sample size of 250 was determined originally through power calculations of the number required for the primary outcome measures (duration of ventilation, oxygen therapy, and hospital stay) in the neonatal trial. The number of patients traced for follow-up evaluation was reduced by the neonatal mortality rate, the difficulty in arranging follow-up monitoring from some of the centers in the original trial, and subsequent contact failures. The final sample of 142 therefore had 80% power to detect a RR of 2.4 for FEV1 >2 SD below the population mean or 2.9 for height >2 SD below the population mean. Furthermore, overlap between the groups caused by open-label steroid use for 39% of the placebo-treated infants and 11% of the dexamethasone-treated infants effectively reduces the power to detect differences in the follow-up study.
Systematic reviews7–9 confirmed that steroids are associated with a reduction in ventilator requirements and CLD in infancy, but only with moderately early treatment was there an accompanying reduction in mortality rates.8 Little respiratory follow-up data are available, with 1 study reporting respiratory symptoms at 5 years with a trend to increased wheezing in the steroid group30 and another study finding no difference in upper respiratory infections at 8 years of age.18 It will be important to have respiratory as well as neurologic outcome data for children treated moderately early, to determine whether their better neonatal outcomes are reflected in long-term benefits. Comparison between inhaled and systemically administered steroids31 suggests that there are fewer adverse effects but also fewer benefits in initial respiratory status. Whether nebulized steroids, much lower doses of systemically administered steroids, or steroids other than dexamethasone32 can be of any benefit to this vulnerable group of children is not known. Any consideration of respiratory outcomes must not be isolated from concerns regarding neurologic outcomes.21
ACKNOWLEDGMENTS
The original controlled trial, the 3-year follow-up study, and the current study were all funded through the generosity of Action Medical Research.
We are indebted to Dr Caroline Beardsmore, Department of Child Health, Leicester Royal Infirmary, who provided training in lung-function measurement for the study nurses and reviewed flow-volume loops. In addition to the acknowledgments in the preceding article, we thank Dr Edward Rocella, National High Blood Pressure Education Program (Bethesda, MD), and Professor Bernard Rosner, Harvard Medical School (Boston, MA), who provided additional age/height-related normative blood pressure data.
FOOTNOTES
Accepted Nov 17, 2005.
No conflict of interest declared.
REFERENCES
Horbar JD, McAuliffe TL, Adler SM, et al. Variability in 28-day outcomes for very low birth weight infants: an analysis of 11 neonatal intensive care units. Pediatrics. 1988;82 :554 –559
Vohr BR, Coll CG, Lobato D, Yunis KA, O'Dea C, Oh W. Neurodevelopmental and medical status of low-birthweight survivors of bronchopulmonary dysplasia at 10 to 12 years of age. Dev Med Child Neurol. 1991;33 :690 –697
Bader D, Ramos AD, Lew CD, Platzker ACG, Stabile MW, Keens TG. Childhood sequelae of infant lung disease: exercise and pulmonary function abnormalities after bronchopulmonary dysplasia. J Pediatr. 1987;110 :693 –699
Northway WH, Moss RB, Carlisle KB, et al. Late pulmonary sequelae of bronchopulmonary dysplasia. N Engl J Med. 1990;323 :1793 –1799
Koumbourlis AC, Motoyama EK, Mutich RL, Mallory GB, Walczak SA, Fertal K. Longitudinal follow-up of lung function from childhood to adolescence in prematurely born patients with neonatal chronic lung disease. Pediatr Pulmonol. 1996;21 :28 –34
Crowley P. Prophylactic corticosteroids for preterm birth [Cochrane review]. In: The Cochrane Library. Issue 3. Chichester, United Kingdom: John Wiley & Sons; 2004
Halliday HL, Ehrenkranz RA, Doyle LW. Early postnatal (<96 hours) corticosteroids for preventing chronic lung disease in preterm infants [Cochrane review]. In: The Cochrane Library. Issue 3. Chichester, United Kingdom: John Wiley & Sons; 2004
Halliday HL, Ehrenkranz RA, Doyle LW. Moderately early (7–14 days) postnatal cortico-steroids for preventing chronic lung disease in preterm infants [Cochrane review]. In: The Cochrane Library. Issue 3. Chichester, United Kingdom: John Wiley & Sons; 2004
Halliday HL, Ehrenkranz RA, Doyle LW. Delayed (>3 weeks) postnatal corticosteroids for chronic lung disease in preterm infants [Cochrane review]. In: The Cochrane Library. Issue 3. Chichester, United Kingdom: John Wiley & Sons; 2004
Carson SH, Taeusch HW Jr, Avery ME. Inhibition of lung cell division after hydrocortisone injection into fetal rabbits. J Appl Physiol. 1973;34 :660 –663
Kotas RV, Mims LC, Hart LK. Reversible inhibition of lung cell number after glucocorticoid injection into fetal rabbits to enhance surfactant appearance. Pediatrics. 1974;53 :358 –361
Navarro HA, Kudlacz EM, Eylers JP, Slotkin TA. Prenatal dexamethasone administration disrupts the pattern of cellular development in rat lung. Teratology. 1989;40 :433 –438
Smolders-de Haas H, Neuvel J, Schmand B, Treffers PE, Koppe JG, Hoeks J. Physical development and medical history of children who were treated antenatally with corticosteroids to prevent respiratory distress syndrome: a 10- to 12-year follow-up. Pediatrics. 1990;85 :65 –70
Jones R, Wincott E, Elbourne D, Grant A. Controlled trial of dexamethasone in neonatal chronic lung disease: a 3-year follow-up. Pediatrics. 1995;96 :897 –906
Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan WJ. Asthma and wheezing in the first six years of life. N Engl J Med. 1995;332 :133 –138
Gibson AT, Pearse RG, Wales JKH. Growth retardation after dexamethasone administration: assessment by knemometry. Arch Dis Child. 1993;69 :505 –509
Yeh TF, Lin YJ, Lin HC, et al. Outcomes at school age after postnatal dexamethasone therapy for lung disease of prematurity. N Engl J Med. 2004;350 :1304 –1313
Abman SH, Warady BA, Lum GM, Koops BL. Systemic hypertension in infants with bronchopulmonary dysplasia. J Pediatr. 1984;104 :928 –931
Collaborative Dexamethasone Trial Group. Dexamethasone therapy in neonatal chronic lung disease: an international placebo-controlled trial. Pediatrics. 1991;88 :421 –427
Jones RAK. Randomized, controlled trial of dexamethasone in neonatal chronic lung disease: 13- to 17-year follow-up study: I. neurologic, psychological, and educational outcomes. Pediatrics. 2005;116 :370 –378
American Thoracic Society. 1995 ATS statement: standardization of spirometry 1994 update. Am J Respir Crit Care Med. 1995;152 :1107 –1136
Rosenthal M, Bain SH, Cramer D, et al. Lung function in white children aged 4 to 19 years, I: spirometry. Thorax. 1993;48 :794 –802
Polgar G, Promadhat V. Pulmonary Function Testing in Children: Techniques and Standards. Philadelphia, PA: WB Saunders; 1971
Child Growth Foundation. British 1990 Growth Reference for Height, Weight, BMI and Head Circumference. London, United Kingdom: Child Growth Foundation; 1990
National High Blood Pressure Education Program Working Group on Hypertension Control in Children and Adolescents. Update on the 1987 task force report on high blood pressure in children and adolescents: a working group report from the National High Blood Pressure Education Program. Pediatrics. 1996;98 :649 –658
Asher MI, Keil U, Anderson HR, et al. International Study of Asthma and Allergies in Childhood (ISAAC): rationale and methods. Eur Respir J. 1995;8 :483 –491
Emery EF, Greenough A. Blood pressure levels at follow-up of infants with and without chronic lung disease. J Perinat Med. 1993;21 :377 –383
Ylihrsil H, Eriksson E, Forsen T, Kajantie E, Osmond C, Barker DJP. Self-perpetuating effects of birth size on blood pressure levels in elderly people. Hypertension. 2003;41 :446 –450
O'Shea TM, Goldstein DJ, Jackson BG, Kothadia JM, Dillard RG. Randomised trial of a 42-day tapering course of dexamethasone in very low birth weight infants: neurological, medical and functional outcome at 5 years of age . Pediatr Res. 2000;47 :319A
Halliday HL, Patterson CC, Halahakoon CWNL. A multicenter, randomized open study of early corticosteroid treatment (OSECT) in preterm infants with respiratory illness: comparison of early and late treatment and of dexamethasone and inhaled budesonide. Pediatrics. 2001;107 :232 –240
Thébaud B, Lacaze-Masmonteil T, Watterberg K. Postnatal corticosteroids in very preterm infants: "the good, the bad, and the ugly " Pediatrics. 2001;107 :413 –415(Rosamond A. K. Jones, MD,)
ABSTRACT
Objectives. To study the growth, health status, and respiratory outcomes at 13 to 17 years of infants enrolled in a double-blind, randomized, controlled trial of dexamethasone for the treatment of neonatal chronic lung disease.
Participants. A total of 287 infants who were chronically dependent on supplementary oxygen between 2 and 12 weeks of age were recruited from 31 centers in 6 countries to a double-blind, randomized, controlled trial of dexamethasone base (0.5 mg/kg per day for 1 week) or placebo, and survivors were evaluated at 3 years. Children from the 25 British and Irish centers were traced for reassessment at 13 to 17 years of age.
Outcome Measures. Respiratory symptoms, lung-function testing, height, weight, head circumference, blood pressure, health resource usage, and school absences.
Results. There was no significant difference in respiratory outcomes between the dexamethasone and placebo groups. Lung function was impaired but with no difference between the 2 groups. Growth was also impaired in both groups, with height z score of –0.7, weight z score of –0.4, and head circumference z score of –1.1. Systolic blood pressure was >95th percentile for age and height for 15% of children, but with no difference between the 2 groups. There was no difference in the numbers of hospital admissions for respiratory causes or other causes.
Conclusions. Despite a shorter duration of neonatal assisted ventilation, there is no evidence that dexamethasone use is associated with long-term improvement in lung function. Impaired growth and poor health status are long-term consequences of neonatal chronic lung disease, irrespective of exposure to neonatal dexamethasone.
Key Words: randomized controlled trial dexamethasone neonatal chronic lung disease follow-up respiratory lung function blood pressure health status growth
Abbreviations: CLD, chronic lung disease FVC, forced vital capacity FEV1, forced expiratory volume in 1 second RR, relative risk CI, confidence interval GP, general practitioner
Neonatal chronic lung disease (CLD) is a common complication of very low birth weight1 and is associated with continuing childhood ill health.2 Survivors assessed in later childhood3 and even into young adult life4,5 may show impaired lung function and also impaired growth. The benefits of prenatal steroid therapy in reducing rates of surfactant-deficient respiratory distress syndrome and improving survival rates are well established.6 Systematic reviews of a large number of randomized trials of steroids, especially dexamethasone, in the prevention or treatment of neonatal CLD have shown reduced duration of assisted ventilation and oxygen therapy.7–9
Theoretically, one might expect that early use of steroids to downregulate the inflammatory response and to decrease the duration of assisted ventilation would lead to earlier resolution of CLD and improved lung function at follow-up evaluations. However, concerns have been raised that steroids given during a phase of rapid lung growth and maturation could have harmful rather than beneficial long-term effects. Fetal rabbits given a single dose of corticosteroid showed impaired lung growth and cell division,10 although this effect disappeared by 1 month of age.11 Newborn rats given multiple doses of glucocorticoid showed changes in lung architecture that persisted into adult life.12 However, follow-up evaluations of infants randomized to receive corticosteroids, whether prenatally13 or postnatally,14 have not demonstrated any significant effect on later respiratory morbidity. A clear link has been shown between small lungs in infancy and subsequent wheezing.15 If somatic growth is impaired, then lung growth may also be affected. Neonatal steroid therapy has been associated with impaired somatic growth during treatment,16 even with short courses of treatment. In one follow-up study, steroid-treated boys were significantly shorter and lighter at 2 years of age than were their placebo-treated counterparts,17 and these same children were shorter and demonstrated smaller head circumference at 8 years of age.18 Others have not demonstrated any significant difference in subsequent growth.14 Systemic hypertension is a recognized complication of neonatal CLD,19 but information on blood pressure in later childhood is lacking. In several studies, neonatal steroid therapy was associated with an increase in blood pressure.7–9 Although this was usually mild, it is not known whether this increase was sustained at a later age.
This report from a large, randomized, controlled trial of neonatal dexamethasone therapy20 is the first to report on health status in adolescence, with particular regard to respiratory symptoms, lung function, blood pressure, and growth. The accompanying article reports on neurodevelopmental and educational status.21
METHODS
Participants
Between 1984 and 1989, 287 infants with neonatal CLD were recruited to an international, randomized, controlled trial of dexamethasone therapy.20 Infants were eligible if they had no major congenital malformations and were dependent on supplementary oxygen, with their condition being static or deteriorating, at 2 to 12 weeks of age (median age: 4 weeks). They were randomized through telephone contact with a central office, with stratification according to center and whether they were still receiving assisted ventilation (61%) or not (39%), to receive either dexamethasone base (0.5 mg/kg per day for 1 week) or placebo, given intravenously or orally and with the option of a second tapering 9-day course. Clinicians were allowed to prescribe open-label dexamethasone if there was life-threatening deterioration, but they remained blinded to the trial treatment allocation. Survivors were evaluated at 3 years of age.14 Children from the 25 British and Irish centers were traced for reassessment at 13 to 17 years of age21 and were contacted through their general practitioners (GPs). Assessments were conducted in the children's own homes between 2001 and 2002; study nurses and families remained blinded to the original treatment allocation.
Research Ethics Committee Approval
Approval for the present study was obtained from the Anglia and Oxford Multicenter Research Ethics Committee, and the appropriate local research ethics committees were informed. Informed consent from the children and their parents was obtained for each aspect of the study.
Assessment Tools
Lung-function testing was conducted with a standard electronic spirometer (Vitalograph Alpha III, Vitalograph Ltd, Buckingham, United Kingdom). The research nurses were all given training in spirometry by an experienced pediatric respiratory physiologist (Caroline Beardsmore). They conducted practice lung-function testing with volunteer children through local schools or pediatric departments, sending flow loops for review, until all 3 nurses were able to recognize satisfactory tracings reliably. Children were asked to avoid using -receptor agonist inhalers for 4 hours before their assessments, but use of steroid inhalers continued as normal. At each home visit, the spirometer was calibrated. Lung-function testing was performed according to the American Thoracic Society standardized protocol.22 Children were instructed and were then asked to perform a complete forced expiration and inspiration, with the child seated and wearing a nose clip. The test was repeated until 3 satisfactory loops had been obtained. The test was abandoned after a maximum of 8 attempts. Inhaled salbutamol (400 μg) was then administered with a spacer device, and the lung-function tests were repeated 15 minutes later. For children unfamiliar with the spacer device, initial practice was performed with a placebo. All flow loops were examined visually. Results were rejected if the 2 best forced vital capacity (FVC) measurements were not within 10% of each other (5% preferred). The best values for FVC and forced expiratory volume in 1 second (FEV1) were selected. The FEV1/FVC ratio was calculated with the best FEV1 and the best FVC. Forced expiratory flow in the middle 2 quartiles of expiration was taken from the loop with the greatest sum of FVC plus FEV1. Any flow-volume loops of questionable quality and a representative sample of all other loops were scrutinized by Caroline Beardsmore, who was blinded to the trial allocation, to ensure standard interpretation by the 3 study nurses. Results were converted into z scores by using published reference ranges for age and height.23,24 Weight was recorded with portable digital scales accurate to 0.1 kg. Height was measured with a Leicester portable height meter, and head circumference was measured with a standard paper tape. These measurements were converted into SD scores (z scores) for the child's age by using national normative data.25 Blood pressure was measured with a portable digital sphygmomanometer (Omron M4, Omron Healthcare [UK] Ltd, Milton Keynes, United Kingdom). Adult and pediatric cuffs were available, and the correct size was chosen. Blood pressure was measured in the right arm, with the child seated. Results were compared with normative data for age, height, and gender among adolescents.26
Health Questionnaires
A health questionnaire was completed by the families and by their GPs, ascertaining respiratory symptoms, other health problems or diagnoses, medications, and GP or hospital attendance. The respiratory symptom questions were taken from a standardized questionnaire.27 All questionnaires are available from the author or electronically (www.npeu.ox.ac.uk/dex).
Sample Size, Outcome Measures, and Statistical Methods
The sample size was predetermined by the size required for the original randomized trial minus any deaths and enrollments from centers outside Britain and Ireland. The primary outcome measures were the proportions of children >2 SD below the mean for FEV1 and for height. A sample size of 195 yielded an 80% chance of showing an increase in incidence in the primary outcomes from 20% to 39% or a decrease to 6%. Secondary respiratory outcome measures included z scores for all lung-function parameters, evidence of reversible airway disease (postsalbutamol FEV1 that was 80% of the predicted value and was increased by 10% over the baseline value), partially reversible airway disease (postsalbutamol FEV1 that was <80% of the predicted value despite an increase of 10% over the baseline value), or fixed airway disease (postsalbutamol FEV1 that was <80% of the predicted value with an increase of <10% over the baseline value), and frequency of respiratory symptoms, inhaler use, and hospital admissions. Other secondary outcome measures included weight, height, BMI, and head circumference z scores and systolic and diastolic blood pressure of >95th percentile and >50th percentile for age, gender, and height. Statistical analyses were performed on an intention-to-treat basis, with SPSS version 11 software (SPSS, Chicago, IL). Results are given as relative risks (RRs) or RR differences with 95% confidence intervals (CIs); the 2 test for trend was used.
RESULTS
Of 287 children recruited, 43 children were from North American or continental European centers not included in this study, consent for the original trial was refused for 3 children, and 46 children died before the 3-year follow-up assessment, leaving 195 eligible children. A total of 145 children (76%) completed a health questionnaire, and Fig 1 gives details of measurements completed. There was no evidence of any differences between the children included in the follow-up study and those not included, in particular with regard to open-label steroid usage.21
Results of lung-function testing are shown in Table 1. Although the majority of children had lung function falling within the normal range, z scores showed that both groups of children had results below those expected for age and height, but with no difference between the 2 groups. The health questionnaire revealed approximately one third of children with a diagnosis of asthma and 24% using antiasthma inhalers, but with no significant differences between the groups (Table 2). Growth and blood pressure measurements are shown in Table 3. The 2 groups of children showed similar reductions in weight, height, and head circumference, compared with normative data for their age. Systolic blood pressure was above the 97th percentile for 15% of children, but with no difference between the 2 groups. There was a high level of reported morbidity in the children, almost one half of whom were still receiving some specialist care (Table 4).
Use of open-label steroids for 39% of the placebo-treated children, compared with 11% of the dexamethasone-treated group, had the potential to reduce any differences between the 2 groups. A secondary analysis was performed for the primary outcome measures for the 2 groups, stratified according to centers' use of open-label steroids (Table 5). There were no significant differences in the risk of low FVC, low FEV1, or low height, or in the ratios of RRs in interaction tests, when children from centers with no, low, or high steroid usage were compared.
DISCUSSION
This study has monitored a group of infants with severe neonatal CLD and has confirmed that large proportions of these children have ongoing respiratory symptoms and impaired lung function in adolescence.4 Koumbourlis et al5 monitored preterm infants through childhood and showed that impaired lung function continued to improve into adolescence, but the authors did not report on steroid usage. Our patients showed reduced ventilator requirements and earlier extubation after neonatal dexamethasone usage.20 However, we have seen no demonstrable effect of sustained benefits for lung function. Conversely, this study showed no evidence that use of steroids in the neonatal period caused long-term lung damage, as suggested by animal studies.12 In particular, FVC was better preserved than FEV1, which would not be the case if alveolar size and numbers were diminished. Constraints on alveolar development are likely to be multifactorial; therefore, any adverse effect of dexamethasone may be small, compared with the adverse effects of preterm birth itself.
This study confirmed the long-term effects on growth associated with neonatal CLD,4 with survivors being shorter and lighter than expected for age. The mean head circumference in adolescence was 1 SD below expected, and this finding is reflected in the higher levels of neurodisability among these children.21 However, no differences in any growth parameters were seen between the dexamethasone group and the placebo group. Blood pressure was increased regardless of treatment allocation. Neonatal hypertension accompanying CLD has been reported to resolve during infancy.28 Hypertension in adult life is, however, an increasingly recognized complication of low birth weight itself.29
As discussed in the accompanying article, the sample size of 250 was determined originally through power calculations of the number required for the primary outcome measures (duration of ventilation, oxygen therapy, and hospital stay) in the neonatal trial. The number of patients traced for follow-up evaluation was reduced by the neonatal mortality rate, the difficulty in arranging follow-up monitoring from some of the centers in the original trial, and subsequent contact failures. The final sample of 142 therefore had 80% power to detect a RR of 2.4 for FEV1 >2 SD below the population mean or 2.9 for height >2 SD below the population mean. Furthermore, overlap between the groups caused by open-label steroid use for 39% of the placebo-treated infants and 11% of the dexamethasone-treated infants effectively reduces the power to detect differences in the follow-up study.
Systematic reviews7–9 confirmed that steroids are associated with a reduction in ventilator requirements and CLD in infancy, but only with moderately early treatment was there an accompanying reduction in mortality rates.8 Little respiratory follow-up data are available, with 1 study reporting respiratory symptoms at 5 years with a trend to increased wheezing in the steroid group30 and another study finding no difference in upper respiratory infections at 8 years of age.18 It will be important to have respiratory as well as neurologic outcome data for children treated moderately early, to determine whether their better neonatal outcomes are reflected in long-term benefits. Comparison between inhaled and systemically administered steroids31 suggests that there are fewer adverse effects but also fewer benefits in initial respiratory status. Whether nebulized steroids, much lower doses of systemically administered steroids, or steroids other than dexamethasone32 can be of any benefit to this vulnerable group of children is not known. Any consideration of respiratory outcomes must not be isolated from concerns regarding neurologic outcomes.21
ACKNOWLEDGMENTS
The original controlled trial, the 3-year follow-up study, and the current study were all funded through the generosity of Action Medical Research.
We are indebted to Dr Caroline Beardsmore, Department of Child Health, Leicester Royal Infirmary, who provided training in lung-function measurement for the study nurses and reviewed flow-volume loops. In addition to the acknowledgments in the preceding article, we thank Dr Edward Rocella, National High Blood Pressure Education Program (Bethesda, MD), and Professor Bernard Rosner, Harvard Medical School (Boston, MA), who provided additional age/height-related normative blood pressure data.
FOOTNOTES
Accepted Nov 17, 2005.
No conflict of interest declared.
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