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PEDIATRICS Vol. 107 No. 2 February 2001, pp. 232-240
,
From the Regional Neonatal Unit, Royal Maternity Hospital and
Departments of * Child Health and Epidemiology and Public Health, The
Queen's University of Belfast, Belfast, Northern Ireland.
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ABSTRACT |
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Top
Abstract
Methods
Results
Discussion
References
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Aim. To compare early (<3 days) with late (>15 days) steroid therapy and dexamethasone with inhaled budesonide in very preterm infants at risk of developing chronic lung disease.
Methods. Five hundred seventy infants from 47 neonatal intensive care units were enrolled. Criteria for enrollment included gestational age <30 weeks, postnatal age <72 hours, and need for mechanical ventilation and inspired oxygen concentration >30%. Infants were randomly allocated to 1 of 4 treatment groups in a factorial design: early (<72 hours) dexamethasone, early budesonide, delayed selective (>15 days) dexamethasone, and delayed selective budesonide. Dexamethasone was given in a tapering course beginning with 0.50 mg/kg/day in 2 divided doses for 3 days reducing by half until 12 days of therapy had elapsed. Budesonide was administered by metered dose inhaler and a spacing chamber in a dose of 400 µg/kg twice daily for 12 days. Delayed selective treatment was started if infants needed mechanical ventilation and >30% oxygen for >15 days. The factorial design allowed 2 major comparisons: early versus late treatment and systemic dexamethasone versus inhaled budesonide. The primary outcome was death or oxygen dependency at 36 weeks and analysis was on an intention-to-treat basis. Secondary outcome measures included death or major cerebral abnormality, duration of oxygen treatment, and complications of prematurity. Adverse effects were also monitored daily.
Results. There were no significant differences among the groups for the primary outcome. Early steroid treatment was associated with a lower primary outcome rate (odds ratio [OR]: 0.85; 95% confidence interval [CI]: 0.61,1.18) but even after adjustment for confounding variables the difference remained nonsignificant. Dexamethasone-treated infants also had a lower primary outcome rate (OR: 0.86; 95% CI: 0.62,1.20) but again this difference remained not significant after adjustment. For death before discharge, dexamethasone and early treatment had worse outcomes than budesonide and delayed selective treatment (OR: 1.42; 95% CI: 0.93,2.16; OR: 1.51; 95% CI: 0.99,2.30 after adjustment, respectively) with the results not quite reaching significance. Duration of supplementary oxygen was shorter in the early dexamethasone group (median: 31 days vs 40-44 days). Early dexamethasone was also associated with increased weight loss during the first 12 days of treatment (52 g vs 3 g) compared with early budesonide, but over 30 days there was no difference. In the early dexamethasone group, there was a reduced incidence of persistent ductus arteriosus (34% vs 52%-59%) and an increased risk of hyperglycemia (55% vs 29%-34%) compared with the other 3 groups. Dexamethasone was associated with an increased risk of hypertension and gastrointestinal problems compared with budesonide but only the former attained significance.
Conclusions. Infants given early treatment and dexamethasone therapy had improved survival without chronic lung disease at 36 weeks compared with those given delayed selective treatment and inhaled budesonide, respectively, but results for survival to discharge were in the opposite direction; however, none of these findings attained statistical significance. Early dexamethasone treatment reduced the risk of persistent ductus arteriosus. Inhaled budesonide may be safer than dexamethasone, but there is no clear evidence that it is more or less effective. Key words: preterm, neonate, chronic lung disease, glucocorticoids, systemic dexamethasone, inhaled budesonide, spacing chamber, randomized clinical trial, bronchopulmonary dysplasia.
Until recently preterm birth has been associated with
relatively high levels of mortality and morbidity. The introduction of
surfactant therapy reduced mortality,1 but the rates of
complications, such as intraventricular hemorrhage and bronchopulmonary
dysplasia (or chronic lung disease [CLD]), have been only moderately
reduced by this intervention.2,3 Approximately 33% of
very low birth weight (<1500 g) infants develop CLD defined as a
requirement for oxygen supplementation beyond 4 weeks.3 At
36 weeks' postmenstrual age the prevalence of CLD varies between 4%
and 22%, depending on the center and its ventilation
practice.4 These infants often have protracted stays in
hospitals and are at increased risk of death or long-term morbidity,
such as failure to thrive and developmental delay with frequent
readmissions to hospitals during the first 1 to 2 years of
life.5,6
Treatment with dexamethasone improves lung function in infants with
CLD, but doubts remain about its long-term efficacy and safety.7-9 In a previous study of infants with
chronic oxygen dependence at 3 weeks of age, dexamethasone
significantly reduced the duration of assisted ventilation in infants
who were ventilator-dependent but mortality, duration of oxygen
supplementation, and length of hospital stay were not
decreased.10 An overview of randomized, controlled trials
of dexamethasone treatment for chronic lung disease in infants of >3
weeks' postnatal age did not show any substantial effects on mortality
before discharge (relative risk [RR]: 1.16; 95% confidence interval
[CI]: 0.76-1.77) but did show a reduced need for later treatment
with steroids (RR: 0.29; 95% CI: 0.11-0.78) in treated
infants.11 Adverse effects included hyperglycemia,
glycosuria, and hypertension.12
More recently dexamethasone has also been used early in the course of
neonatal respiratory distress.13,14 Overviews of early
steroid treatment either before 4 days15 or between 7 and
14 days16 show significant benefits of more rapid weaning
from the ventilator and a reduction in CLD at 28 days or 36 weeks' postconceptional age.12 For infants treated at
7 to 14 days, there was also an improvement in survival at 28 days (RR: 0.46; 95% CI: 0.25-0.82). However, significant adverse
effects were found including gastrointestinal bleeding, hyperglycemia,
hypertension, hypertrophic cardiomyopathy, and intestinal
perforation.12 There are other concerns about long-term
effects of corticosteroids on brain development17 that
warrant caution in using this treatment early in life without good
scientific evidence of beneficial acute effects. Indeed, 2 recent
clinical studies have suggested that long courses of postnatal steroids
are associated with an increased risk of cerebral palsy.18,19
Recently inhaled steroids have been used to treat or attempt to prevent
CLD in the belief that topical treatment would be associated with fewer
adverse systemic effects.20 One recently published study
suggested that inhaled beclomethasone reduced the need for systemic
dexamethasone therapy and mechanical ventilation at 28 days.21 However, a recent overview of trials of inhaled
steroids concluded that although there were short-term beneficial
effects with improved lung function and less need for later systemic
steroids there were no apparent long-term benefits and no effect on
mortality or risk of CLD.12
Our study was designed in 1993 at a time when it was generally believed
that postnatal corticosteroids were beneficial and that an untreated
control group was unnecessary. The uncertainties about steroid therapy
in the newborn centered around timing and type of drug. The factorial
design of our study allowed for 2 comparisons: 1) early (<72 hours)
versus late (>15 days) steroids and 2) systemic dexamethasone versus
inhaled budesonide.
Infants were eligible for inclusion if they fulfilled the
following criteria: 1) gestational age <30 weeks (see also point 4);
2) postnatal age <72 hours; 3) endotracheal intubation needed; 4)
inspired oxygen concentration >30%, but infants of 30 and 31 weeks
could also be included if they needed >50% oxygen; 5) no contraindication to enrollment: including lethal congenital
anomalies, severe intraventricular hemorrhage (grades III or IV),
and proven systemic infection before entry; a strong suspicion of
infection and uncontrolled hypertension or hyperglycemia were
considered to be indications to postpone trial entry until they
resolved, provided that this occurred within 72 hours of birth; and 6)
parental consent. Infants could be enrolled either before of after
treatment with surfactant. The study group was selected because of its
high risk of developing CLD.
Once an infant had fulfilled the entry criteria, the supervising
clinician telephoned the randomization center in Belfast to enroll the
infant and determine the treatment group. There were 4 treatment
groups: early (<72 hours) dexamethasone, early (<72 hours)
budesonide, delayed selective (>15 days) dexamethasone, and delayed
selective (>15 days) budesonide. Infants randomized to the delayed
selective groups needed to fulfill the above entry criteria at 15 days
of age to be eligible for treatment.
Dexamethasone was administered intravenously or orally in an initial
dose of 0.50 mg/kg/day in 2 divided doses for 3 days, followed by 0.25 mg/kg/day in 2 divided doses for 3 days, then 0.10 mg/kg/day in 2 divided doses for 3 days, and finally 0.05 mg/kg/day in 2 divided doses
for 3 days; that is, a total of 12 days of drug treatment. Budesonide
was administered using a metered dose inhaler (MDI; 200 µg/puff;
Pulmicort, Astra Draco, Lund, Sweden) connected to a spacing device
(Aerochamber MV 15; Trudell Medical, Canada). The Aerochamber is a
rigid, clear plastic cylinder, 11 by 4.1 cm with an approximate
capacity of 145 mL. After bronchopulmonary suctioning the MDI was
shaken vigorously and inserted into the spacing chamber. The spacer was
then filled with 100% oxygen and the infant's inspired oxygen
concentration was increased by 20% (for example, from 50% to 70%
oxygen). The Aerochamber was then inserted into the ventilator circuit
close to the endotracheal tube.22 Manual inflations were
given through the chamber using an inflatable bag and as soon as chest
movements were well established the budesonide was administered from
the MDI. The dose was calculated according to the infant's weight (400 µg/kg twice daily). A 500- to 1000-g infant was given 400 µg (2 puffs) twice daily and a 1000- to 1500-g infant 600 µg (3 puffs)
twice daily. The puffs were given one at a time, activating the MDI at
end-expiration and allowing 10 breaths after each activation. After
each administration, the chamber was removed from the ventilator
circuit and the infant was reconnected to the ventilator at the
previous settings. The duration of budesonide treatment was up to 12 days provided the infant remained intubated. Extubation before 12 days
was an indication to discontinue budesonide.
The study design was open rather than double-blind because some
clinicians wanted to prescribe broad spectrum antibiotics and/or
H2 blockers such as
cimetidine or ranitidine to infants receiving dexamethasone. However,
in 11 centers, the trial was conducted double-blind, and in these
centers placebo MDIs and intravenous saline were used to mask treatment
allocation. The primary outcome measure was death or oxygen dependency
at 36 weeks' postconceptional age. Secondary outcome measures included
death or major cerebral abnormality on ultrasound scan nearest to 6 weeks, death or oxygen dependency at 28 days and expected date of
delivery (EDD), duration of >40% oxygen, duration of any supplemental oxygen, duration of assisted ventilation by endotracheal tube, and
duration of hospital stay. Complications such as pneumothorax or other
pulmonary air leak, necrotizing enterocolitis, acquired pneumonia,
persistent ductus arteriosus requiring treatment, pulmonary hemorrhage
requiring increased ventilation, seizures treated with anticonvulsants,
recurrent apnea needing treatment, retinopathy of prematurity at 36 weeks, gastric hemorrhage, and gastrointestinal perforation were
additional secondary outcome measures that were collected
prospectively.
In addition there was monitoring for adverse events by recording a
daily blood pressure nearest to midday, daily blood glucose estimate by
stick method nearest midday and withdrawals from the trial because of
hypertension, hyperglycemia, sepsis, gastric bleeding, or intestinal
perforation.
Data were collected during the first 12 hours of life to allow
calculation of the Clinical Risk Index for Infants score, a measure of
disease severity and predictor of neonatal survival.23
Statistical Analysis
The trial had a factorial design with equal proportions of
infants allocated to each combination of 2 factors according to the
scheme:
Group 1 2 3 4 Factor
1 Type of
Steroid Dexamethasone Dexamethasone Budesonide Budesonide Factor
2 Timing of Steroid Early Delayed
selective Early Delayed selective
Although the trial had the potential to detect an
interaction between the type and timing of steroid treatment (for
example, that one steroid performs better, but only if given early),
the sample size calculations were based on the assumption that there would be no such interaction. That being the case, the aim was to
combine the treatment groups to answer 2 separate questions: 1) which
type of steroid is better? (groups 1 and 2 vs groups 3 and 4), and 2)
is early or delayed selective administration better? (groups 1 and 3 vs
groups 2 and 4).
Sample size was calculated on the basis that the expected rate of death
or survival with CLD would be ~30% as in a previous study.24 Assuming that a change in the type or timing of
steroid treatment reduced the rate of adverse outcome by one quarter
from the expected rate of 30%, then a sample size of 1130 would have
80% power to detect this reduction as significant (P < .05, 2-tailed). However, during the study it became apparent that
the actual rate of death or oxygen dependency at 36 weeks was ~60%
and recalculation of the sample size using a power of 90% and a
similar reduction (one quarter) in the rate of the primary outcome from
60% to 45% gave the number of infants to be recruited as 500.
Analysis of all outcomes was according to the intention-to-treat
principle. A single interim analysis was planned when one half of the
infants had been recruited and the Data Monitoring Committee included
the trial statistician and a pediatrician otherwise uninvolved with the
study (see "Appendix").
Comparisons of baseline variables among the 4 randomized groups were
conducted using tests appropriate for the scale of measurement (1-way
analysis of variance, Kruskal-Wallis analysis of variance of ranks, or
the Comparisons of outcomes between dexamethasone and budesonide and
between early treatment and delayed selective treatment were initially
obtained by pooling the appropriate treatment groups and using
Five hundred seventy infants were enrolled in the study between
February 1994 and December 1998 from 47 hospitals worldwide ("Appendix"). Demographic details by study group are shown in Table
1. Apart from gender distribution, there
were no significant differences in obstetric or neonatal demographic
data by allocated study group. By chance, fewer male infants were
allocated to the early budesonide group. When groups were aggregated
into early and delayed selective and dexamethasone and budesonide, there were no differences in obstetric or neonatal variables. More than
93% of infants had been treated with surfactant before enrollment.
TABLE 1
METHODS
Top
Abstract
Methods
Results
Discussion
References
2 test for contingency tables).
2 tests for 2 × 2 tables. Odds ratios
(ORs) and 95% CIs were also obtained. Further analysis to test for
interaction between the steroid type (dexamethasone or budesonide) and
treatment timing (early or delayed selective) was obtained using
logistic regression analysis. This approach also permitted all
treatment comparisons to be adjusted for chance imbalance at baseline.
Adjusted ORs were obtained after allowing for the following potential
confounding variables: gestation, birth weight, gender, maternal
steroids, multiple birth, birth place, method of delivery, Apgar score
at 5 minutes, and Clinical Risk Index for Infants score.23
Significance was assessed using likelihood ratio tests conducted at the
5% level and ORs with 95% CIs were also obtained.
RESULTS
Top
Abstract
Methods
Results
Discussion
References
Demographic Data on Study Population by Treatment Allocation
Full courses of steroids, defined as at least 20 doses, were received by a minority of infants (Fig 1). In the early treatment groups, >95% received either a full course or a partial course. In the delayed selective treatment, groups ~60% received no steroids. Overall, the commonest reason for not completing a full course of treatment was death (n = 83; 15%) and the next was extubation before the course could be completed (n = 47; 8%), which applied mainly to the budesonide groups (n = 40; 14%).
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The results of analysis of primary and major secondary outcomes by treatment allocation are shown in Table 2. There were no significant differences among the groups for the primary outcome of death or oxygen dependency at 36 weeks' postconceptional age, although the early dexamethasone group had the lowest proportion of infants with this combined adverse outcome. There was no significant interaction between the type and the timing of steroid treatment. For the aggregated groups early steroid treatment was associated with a lower rate of death or oxygen dependency at 36 weeks (OR: 0.85; 95% CI: 0.61,1.18; P = .33) but even after adjustment for confounding variables the difference was not significant. Dexamethasone-treated infants had a lower rate of death or oxygen dependency at 36 weeks (OR: 0.86; 95% CI: 0.62,1.20; P = .37) but again this difference was not significant even after adjustment (Table 2). We analyzed the comparisons of primary outcomes for the 181 infants enrolled in the 11 centers that used masking of treatment allocation and their results were not significantly different from the rest (steroid effect, P = .49; timing effect, P = .89). Adjustment for confounding variables did not alter these results materially.
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The secondary outcomes of death or oxygen dependency at 28 days also favored both early treatment and dexamethasone rather than delayed selective treatment and budesonide respectively but the differences between groups were not statistically significant. For death or oxygen dependency at EDD, there were again no significant differences, although outcome was slightly worse in the early treated group (OR: 1.04; 95% CI: 0.74,1.47; P = .80). For the outcome death before discharge, the analyses show that dexamethasone and early treatment had worse outcomes than budesonide and delayed selective treatment (OR: 1.42; 95% CI: 0.93,2.16; P = .10; OR: 1.51; 95% CI: 0.99-2.30; P = .054 after adjustment, respectively) with the results not quite reaching significance (Table 2). For the combined outcome of death before discharge or known major cerebral abnormality, both early treatment and dexamethasone tended to increase the risk but the differences were not significant. Four other secondary outcomes of duration of oxygen supplementation, endotracheal intubation, and hospital stay are shown in Table 3. There were clear trends toward reduced durations of oxygen and ventilation for the early dexamethasone group and this was significant for any oxygen (median: 31 days vs 40-44 days; P = .03). When only survivors are considered, duration of oxygen was also shorter in the early dexamethasone group (median: 41 days vs 54-57 days; P = .06), although not quite significant. Early dexamethasone was associated with increased weight loss during the first 12 days of treatment (52 g vs 3 g; P < .001) compared with early budesonide but over 30 days there were no differences in weight gain (Table 4).
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Complications of prematurity and its treatment are shown in Table
5. The analysis of persistent ductus
arteriosus showed a significant interaction between steroid treatment
and timing (P < .001) indicating a reduced incidence
only in the early dexamethasone group (34% vs 52%-59%;
P < .001). There was an almost significant increased
risk of pneumothorax in the early steroid-treated group compared with
delayed selective treatment (OR: 1.51; 95% CI: 0.98-2.34;
P = .06). The increased risk was apparent with both
steroid drugs. There was a reduced risk of retinopathy of prematurity
for early treatment and dexamethasone but the differences were not
significant. Gastrointestinal side effects were also more common in the
dexamethasone-treated groups but the differences were not significant.
Hypertension and hyperglycemia were each assessed by 2 different
methods that demonstrated that dexamethasone treatment led to a
significantly increased risk of both adverse effects compared with
budesonide (Table 6). Early treatment also tended to increase the risk of hypertension and hyperglycemia but
the difference was significant only for hyperglycemia using a
definition of blood glucose 
10 mmol/L compared with delayed selective
treatment (OR: 1.43; 95% CI: 1.01,2.04; P = .05). For this adverse effect, there was a significant interaction
(P = .006) suggesting that early dexamethasone
treatment was particularly likely to cause hyperglycemia.
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The above results are based on intention-to-treat analyses. In 5% of cases, there was a deviation from protocol. The reasons are shown in Table 7 and the commonest was early treatment with dexamethasone in infants randomized to have delayed selective treatment. Analysis of the primary and secondary endpoints for the 95% of infants who were not protocol deviators gave similar results to the whole population studied.
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Causes of death are shown in Table 8. Acute respiratory failure, infection, and intraventricular hemorrhage were the 3 most common causes accounting for 65% of the deaths.
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DISCUSSION |
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Results
Discussion
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Infants recovering from respiratory distress syndrome have increasing levels of proinflammatory cytokines in bronchoalveolar fluid, and it is likely that this inflammatory response plays an important role in the development of CLD.25 In other infants who do not have significant early respiratory distress, there is evidence of exposure to proinflammatory cytokines in utero as a result of chorioamnionitis.26 In very immature infants even resuscitation at birth may release cytokines from the lung triggering an inflammatory response leading to CLD.27
Corticosteroids have been used to either prevent or treat CLD28,29 and their primary action is probably as antiinflammatory agents.30 Possible mechanisms of corticosteroid action on the neonatal lung include increased surfactant and antioxidant synthesis, inhibition of prostaglandin and leukotriene synthesis, and reduced cytokine-mediated inflammation.30 Most studies of corticosteroid treatment in the preterm newborn have used a powerful drug, dexamethasone given either early15,16,29 or late11 after CLD has developed. Concerns about adverse effects of this powerful drug have led clinicians to study various inhaled steroids12 but until recently there were no large studies21 and those comparing inhaled and systemic steroids had small sample sizes.12,31 The study by Cole et al21 compared inhaled beclomethasone with placebo in 253 preterm infants but it failed to demonstrate a reduction in CLD despite decreasing the need for mechanical ventilation at 28 days. Another problem with most previous trials of corticosteroids in the newborn is frequent crossover, so that control infants are often later given steroids.31
The Open Study of Early Corticosteroid Treatment study was designed in 1993 to overcome the problem of inadequate sample size of previous studies; it was planned to be large enough to detect clinically important differences in outcome between early and late steroid treatment and between systemic dexamethasone and inhaled budesonide. The factorial design allowed both these comparisons to be made using the same sample of infants and in addition allowed us to test for interaction. We encountered some problems during the course of the study. First, recruitment was slower than expected and we attribute this to widespread use of natural surfactants, often given very soon after birth, which frequently reduced inspired oxygen requirements during the first 3 days of life to below 30%. This meant that some quite ill infants did not fulfill the study's entry criteria and could not be enrolled. Collaborators were reminded that they could enter infants before giving surfactant but this happened infrequently as 93% of infants studied had been treated with surfactant before enrollment. Second, we encountered crossover as a problem that had been found in previous studies.31 Third, only 42% of infants randomized to have delayed selective treatment actually received it, because they had either died before the age of 15 days or they no longer fulfilled the criteria for treatment at that age. This emphasizes that our study was designed to compare a policy of early treatment with one of late or delayed treatment in selected infants whose lung disease remained severe at 15 days of age. Fourth, the inhaled budesonide groups were at some disadvantage in that they could not be given the drug once they had been extubated. This meant that the treatment courses for budesonide were sometimes <12 days.
Our study was open rather than double-blinded, but 30% of infants were enrolled in centers that used placebo MDI and intravenous saline to allow masking of intervention and outcome assessment. There were no differences in the primary outcome between those observing a double-blind strategy and others. We, therefore, believe that our open study design was unlikely to have lead to large biases.
As regards the major primary outcome the group with the lowest rate of death or oxygen dependency at 36 weeks was early dexamethasone and the one with the highest was delayed selective budesonide. In contrast, survival rate was greatest in the delayed budesonide group and lowest in the early dexamethasone group. This suggests that the major impact of early dexamethasone is in reducing oxygen dependency or CLD as has been shown in the meta-analyses of previous trials.15,28,29 Early dexamethasone does not seem to improve survival15 and indeed there are now concerns that its use might also increase the rate of cerebral palsy.18,19
Another potential benefit of early steroids was a reduction in the incidence of persistent ductus arteriosus, which has previously been shown in the meta-analyses.12,15 The finding of an apparent increased risk of pneumothorax with early steroid treatment was unexpected because previous studies had suggested a reduction in the incidence of pulmonary air leaks.12,15 The increased risk of pneumothorax occurred with both dexamethasone and budesonide and, therefore, is unlikely to have been because of rapidly improving lung compliance.
Our study showed generally low rates of gastrointestinal side effects, including gastric bleeding and perforation, with no significant differences among groups, which is reassuring as previous studies suggested an increased risk with early steroid treatment.12,14,15,32 Indeed one large North American trial was recently stopped because of an excess of gastrointestinal complications in the treatment group.32
It is still not possible to provide firm guidelines for the use of postnatal steroid treatment. Neonatologists must balance the benefits of earlier extubation, reduced risks of CLD, and perhaps improved survival when steroids are given between 7 and 14 days after birth16 against the potential risks of adverse neurodevelopmental outcome especially when steroids are given early after birth.30 Inhaled steroids may prove to be a safer option, but there is no clear evidence from either our study or a systematic review33 that they are more effective than dexamethasone. More long-term follow-up studies of infants enrolled in randomized trials of postnatal steroids are needed, and such a study of survivors from the Open Study of Early Corticosteroid Treatment is currently planned. Until then, postnatal steroids should be used with caution and reserved for infants who are ventilator-dependent and likely to die without them.
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APPENDIX |
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Steering Committee: Henry L. Halliday, William O. Tarnow-Mordi, Rosamund A. Jones, and Michael Silverman
Data Monitoring Committee: Chris C. Patterson and John A. Dodge
Participating Investigators (European Multicenter Steroid Study Group): Aghia Sophia Children's Hospital, Athens, Greece, Costas Papagaroufalis, Marietta Xanthou; Aker Hospital, Oslo, Norway, Andrew Whitelaw; Al Corniche Hospital, Abu Dhabi, UAE, Peter M. Barnes, Adil I. Shubbar; Ayrshire Central Hospital, Irvine, United Kingdom, Sheena Kinmond; Bnai-Zion, Haifa, Israel, David Bader; City Hospital, Stoke on Trent, United Kingdom, S. Andrew Spencer; Dudley Road Hospital, Birmingham, United Kingdom, Jeffrey G. Bissenden; Erinville Hospital, Cork, Ireland, C. Anthony Ryan; Fairfield Hospital, Bury, United Kingdom, Daniel T. Hindley; Foothills Hospital, Calgary, Canada, Doug McMillan; Fredrikstad Hospital, Norway, Inger E. Silberg; Glan Clwyd Hospital, Rhyl, United Kingdom, Tom D. Yuile, Peter R. Stutchfield; Hammersmith Hospital, London, United Kingdom, Richard H. M. Mupanemunda, Michael Silverman; Hospital Criancas Maria, Porto, Portugal, Manuel R. G. Carrapato; Jewish General Hospital, Quebec, Canada, Lajos Kovacs; Jubilee Maternity Hospital, Belfast, United Kingdom, Richard J. Tubman; Kandang Hospital (later KK Women's and Children's Hospital) Singapore, V. Samuel Rajadurai, V. K. Pradeepkumar, Tan K. Wee; Kent and Canterbury, Hospital, Canterbury, United Kingdom, Neil D. Martin; King George Hospital, Goodmayes, United Kingdom, David Robinson, Jo Solebo; Kristiansand Hospital, Norway, Kare Danielsen; Largo Hospital, Oporto, Portugal, Maria A. Areias; Mayday Hospital, Thornton Health, United Kingdom, Yuk L. Chang, John Chang; Ninewells Hospital, Dundee, United Kingdom, William O. Tarnow-Mordi; Northwick Park Hospital, London, United Kingdom, Ros Thomas; Nottingham City Hospital, Nottingham, United Kingdom, David A. Curnock; Orebro Hospital, Orebro, Sweden, Goran Wesstrom; Quebec Hospital, Quebec, Bruno Piedboeuf; Rikshospitalet, Oslo, Norway, Sverre Medboe; Royal Gwent Hospital, Newport, United Kingdom, S. David Ferguson; Royal Maternity Hospital, Belfast, United Kingdom, Chrishanti Halahakoon, Henry L. Halliday; Rushgreen Hospital, Harold Wood, United Kingdom, Jeewan Rawal; San Joao Hospital, Oporto, Portugal, Hereilia Guimares; Santa Maria Hospital, Oporto, Portugal, Maria A. Vaz Guedes; Slajmerjeva, Llubjiana, Slovenia, Janez Babnik; South Manchester University Hospital, Manchester, United Kingdom, Stephen A. Roberts; Southern General Hospital, Glasgow, United Kingdom, Peter D. MacDonald; St Helier Hospital, Carshalton, United Kingdom, Khalid N. Haque; Taunton and Somerset Hospital, Taunton, United Kingdom, Timothy J. French, James Moorcraft; Tonsberg Hospital, Tonsberg Norway, Alf Meberg; Ulster Hospital, Dundonald, United Kingdom, Angela H. Bell; University Hospital of Wales, Cardiff, United Kingdom, Patrick H. T. Cartlidge, Mark R. Drayton; University Hospital, Nottingham, United Kingdom, Judith Grant; University Hospital, Saskatoon, Canada, Koravangattu Sankaran; University Hospital, Zurich, Switzerland, Helmut Oswald, Gabriel Duc, Romaine Arlettaz, Jean-Claude Fauchere; University Medical Hospital, Poznan, Poland, Ewa Burchardt, Janusz Gadzinowski; Victoria Hospital, Blackpool, United Kingdom, Roy Stevens; and Waveney Hospital, Ballymena (later Antrim Area Hospital), United Kingdom, John G. Jenkins.
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ACKNOWLEDGMENTS |
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This study was supported by a grant from Action Research, United Kingdom.
This study was also supported by Trudell Medical, London, Ontario, Canada, which supplied the Aerochambers, and by Astra Draco, Lund, Sweden, which supplied the MDIs of budesonide and placebo.
We thank Samantha Jameson for typing the manuscript, Jean Smith-Davidson for data entry, and Dr Ernie Turkington for statistical preparation.
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FOOTNOTES |
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Received for publication May 1, 2000; accepted Jul 31, 2000.
Reprint requests to (H.L.H.) Regional Neonatal Unit, Royal Maternity Hospital, Grosvenor Rd, Belfast BT12 6BB, Northern Ireland. E-mail: h.halliday{at}qub.ac.uk
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ABBREVIATIONS |
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CLD, chronic lung disease; RR, relative risk; CI, confidence interval; MDI, metered dose inhaler; EDD, expected date of delivery; OR, odds ratio.
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REFERENCES |
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a two-year follow-up study. Pediatrics.
1998;101(5). URL: http://www.pediatrics.org/cgi/content/full/101/5/e7This article has been cited by other articles:
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  S. Basu, A. Kumar, B. D. Bhatia, K. Satya, and T. B. Singh Role of Steroids on the Clinical Course and Outcome of Meconium Aspiration Syndrome A Randomized Controlled Trial J Trop Pediatr, October 1, 2007; 53(5): 331 - 337. [Abstract] [Full Text] [PDF]
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 M. E. Hartnett, D. J. Martiniuk, Y. Saito, P. Geisen, L. J. Peterson, and J. R. McColm Triamcinolone Reduces Neovascularization, Capillary Density and IGF-1 Receptor Phosphorylation in a Model of Oxygen-Induced Retinopathy Invest. Ophthalmol. Vis. Sci., November 1, 2006; 47(11): 4975 - 4982. [Abstract] [Full Text] [PDF]
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 T. T. Wilson, L. Waters, C. C. Patterson, C. G. McCusker, N. M. Rooney, N. Marlow, and H. L. Halliday Neurodevelopmental and Respiratory Follow-up Results at 7 Years for Children From the United Kingdom and Ireland Enrolled in a Randomized Trial of Early and Late Postnatal Corticosteroid Treatment, Systemic and Inhaled (the Open Study of Early Corticosteroid Treatment). Pediatrics, June 1, 2006; 117(6): 2196 - 2205. [Abstract] [Full Text] [PDF]
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R. A. K. Jones and on behalf of the Collaborative Dexamethasone Trial Randomized, Controlled Trial of Dexamethasone in Neonatal Chronic Lung Disease: 13- to 17-Year Follow-up Study: I. Neurologic, Psychological, and Educational Outcomes Pediatrics, August 1, 2005; 116(2): 370 - 378. [Abstract] [Full Text] [PDF]
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R. A. K. Jones and on behalf of the Collaborative Dexamethasone Trial Randomized, Controlled Trial of Dexamethasone in Neonatal Chronic Lung Disease: 13- to 17-Year Follow-up Study: II. Respiratory Status, Growth, and Blood Pressure Pediatrics, August 1, 2005; 116(2): 379 - 384. [Abstract] [Full Text] [PDF]
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 N. A. Parikh, R. G. Locke, A. Chidekel, K. H. Leef, J. Emberger, D. A. Paul, and J. L. Stefano Effect of Inhaled Corticosteroids on Markers of Pulmonary Inflammation and Lung Maturation in Preterm Infants With Evolving Chronic Lung Disease J Am Osteopath Assoc, March 1, 2004; 104(3): 114 - 120. [Abstract] [Full Text] [PDF]
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 F. A. McAlister, S. E. Straus, D. L. Sackett, and D. G. Altman Analysis and Reporting of Factorial Trials: A Systematic Review JAMA, May 21, 2003; 289(19): 2545 - 2553. [Abstract] [Full Text] [PDF]
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 Other Articles Noted Evid. Based Nurs., October 1, 2001; 4(4): E1 - 11. [Full Text] [PDF]
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