PEDIATRICS Vol. 122 No. 1 July 2008, pp. 92-101 (doi:10.1542/peds.2007-2258)
ARTICLE |
Effects of Higher Versus Lower Dexamethasone Doses on Pulmonary and Neurodevelopmental Sequelae in Preterm Infants at Risk for Chronic Lung Disease: A Meta-analysis
a Department of Neonatology
b Center for Pediatric Clinical Epidemiology, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSAPPENDIX: DESCRIPTION OF...REFERENCES |
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OBJECTIVES. Systemic postnatal dexamethasone treatment reduces the risk of chronic lung disease in preterm infants but also may be associated with increased risk of neurodevelopmental impairment. Because it is not known whether these effects are modulated by the cumulative dexamethasone dose, we systematically reviewed the available randomized evidence on the effects of lower versus higher cumulative dexamethasone doses, in terms of death, pulmonary morbidity, and neurodevelopmental outcomes, in preterm infants.
METHODS. Randomized, controlled trials comparing higher- versus lower-dosage dexamethasone regimens in ventilated preterm infants were identified by searching the main electronic databases, references from relevant studies, and abstracts from the Societies for Pediatric Research (from 1990 onward). Eligibility and quality of trials were assessed, and data on study design, patient characteristics, and relevant outcomes were extracted.
RESULTS. Six studies that enrolled a total of 209 participants were included; 2 studies contrasted cumulative dexamethasone doses in the higher ranges (>2.7 mg/kg in the higher-dosage regimen) and 4 in the lower ranges (
2.7 mg/kg in the higher-dosage regimen). Meta-analysis revealed no effect of dexamethasone dose on rates of death and neurodevelopmental sequelae in these 2 subgroups. Subgroup analysis of the studies contrasting dexamethasone doses in the higher ranges showed that the higher dose of dexamethasone was more effective in reducing the occurrence of chronic lung disease than was the lower dose. Interpretation of these data was hampered by the small samples of randomly assigned children, heterogeneity of study populations and designs, use of late rescue glucocorticoids, and lack of long-term neurodevelopmental data in some studies.
CONCLUSIONS. Recommendations for optimal dexamethasone doses for preterm infants at risk for chronic lung disease cannot be based on current evidence. A well-designed, large, randomized, controlled trial is urgently needed to establish the optimal dexamethasone dosage regimen.
Key Words: chronic lung disease • cerebral palsy • glucocorticoids • systematic review • dosage regimen
Abbreviations: CLD—chronic lung disease • PMA—postmenstrual age • RCT—randomized, controlled trial • MDI—Mental Developmental Index • RR—relative risk • CI—confidence interval
Chronic lung disease (CLD), defined as oxygen dependence at postmenstrual age (PMA) of 36 weeks, remains an important complication of prematurity, with a reported incidence of 8% to 35%.1,2 In addition to direct mechanical injury caused by artificial ventilation and oxygen toxicity, pulmonary inflammation has been identified as an important factor in the development of CLD.3–5 Since the 1980s, several randomized, controlled trials (RCTs) have investigated the use of glucocorticoids, in particular dexamethasone, as a means to reduce the incidence of CLD. Some of these trials started glucocorticoid therapy in the first week of life (early), with the aim of preventing progression of the initial acute inflammatory response.6 Others used glucocorticoid therapy for infants who had evolving CLD, starting administration at 7 to 14 days (moderately early), or established CLD, starting >3 weeks after birth (delayed).7,8
The current Cochrane reviews of these RCTs clearly showed that systemic glucocorticoids, mainly dexamethasone, significantly reduced the incidence of CLD and the rate of the combined outcome of CLD or death in preterm infants at risk, independent of the time of postnatal administration.9–11 At the end of the 1990s, however, the first reports of long-term neurodevelopmental outcomes were published, showing that postnatal systemic dexamethasone treatment was associated with increased risk of abnormal neurologic development.12,13 In response to those reports, the American Academy of Pediatrics, the Canadian Paediatric Society, and the European Association of Perinatal Medicine concluded that routine use of systemic dexamethasone for the treatment of CLD could not be recommended until additional research established the optimal type, dose, and timing of glucocorticoid therapy.14,15
However, dexamethasone is still used in most clinical settings around the world.16–19 In an attempt to determine the optimal dose for postnatal dexamethasone treatment (ie, the dose reducing the incidence of CLD without increasing the risk of adverse effects), some studies compared the effects of higher-dosage and lower-dosage regimens of dexamethasone on outcome parameters.20–25 Given the small number of patients included in those individual RCTs, we concluded that a systematic review with a meta-analysis would be needed to establish whether the currently available evidence could identify the optimal dose of dexamethasone or whether additional studies are needed.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSAPPENDIX: DESCRIPTION OF...REFERENCES |
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By using the search strategy of the Cochrane Neonatal Review Group, studies were identified through electronic searches of the Medline (from 1966 onward), Embase (from 1974 onward), and Cinahl (from 1982 onward) databases and the Cochrane Library, using the terms "steroid," "glucocorticoid," and "dexamethasone." Previous review articles and the abstracts of the Society for Pediatric Research and the European Society for Pediatric Research from 1990 onward were hand-searched.
To be included in the meta-analyses, the studies needed to meet the following criteria. (1) The study was a RCT involving ventilated preterm infants. (2) The intervention was a standardized, nonindividualized, higher-dosage regimen of systemic dexamethasone treatment, compared with a lower-dosage regimen. Studies using different types of glucocorticoids (hydrocortisone and methylprednisolone) or inhalation glucocorticoids were excluded because a direct dose comparison of these steroids and administration routes with intravenous dexamethasone doses is not possible. (3) The studies reported 
1 of the following outcome parameters: death, CLD, or long-term neurodevelopmental sequelae.
Two authors (Drs Onland and De Jaegere) evaluated the full text of the relevant reports and assessed the methodologic quality according to the following criteria: allocation concealment, blinding of intervention, completeness of follow-up monitoring, and blinding of outcome measurements. For each study, the following data and outcome parameters were extracted independently by 2 reviewers (Drs Onland and De Jaegere): patient characteristics (such as birth weight, gestational age, and gender); number of patients randomly assigned; prenatal glucocorticoid and postnatal surfactant treatment; dexamethasone regimens (postnatal age at start, duration of therapy, and cumulative dose); duration of mechanical ventilation and failure to extubate at day 3 and day 7 after initiation of therapy; rescue treatment with glucocorticoids outside the study period; death at PMA of 36 weeks and/or at hospital discharge; CLD, defined as oxygen dependence at PMA of 36 weeks; incidence rates of hypertension, sepsis, and hyperglycemia during hospitalization; and long-term neurodevelopmental sequelae, including cerebral palsy, Bayley's Mental Developmental Index (MDI) values, and blindness or poor vision. The original investigators of the included RCTs were asked to verify that data extraction was correct and, if possible, to provide any missing data.
After data extraction, it became clear that 2 studies contrasted dexamethasone doses in the higher ranges and 4 studies in the lower ranges. The highest cumulative dose used in the latter 4 trials was 2.7 mg/kg, which was the lowest dose used in the 2 trials contrasting dexamethasone in the higher ranges. Given this heterogeneity in dexamethasone comparisons, we decided to divide the studies into 2 subgroups, using the arbitrary cutoff point of 2.7 mg/kg to define the high- and low-range subgroups. Studies were assigned to the high-range subgroup if the cumulative dexamethasone dose used in the higher dosage regimen was >2.7 mg/kg and to the low-range subgroup if the cumulative dose used in the higher dosage regimen was 2.7 mg/kg. All statistical analyses were performed for each subgroup separately.
Meta-analyses of the extracted data were performed by using the standard methods of the Cochrane Collaboration and Stata 9.2 (Stata Corp, College Station, TX). Treatment effects for the dichotomous outcomes were expressed as relative risks (RRs) with 95% confidence intervals (CIs) and numbers needed to treat. Weighted mean differences were used for continuous outcomes. In the absence of heterogeneity, a fixed-effects model was used for the meta-analysis; if heterogeneity was noted, then a random-effects model was used.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSAPPENDIX: DESCRIPTION OF...REFERENCES |
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Study Characteristics
A total of 11 articles were identified by using the aforementioned search strategy. The unpublished article by Ariagno and colleagues reported in the Cochrane review by Halliday et al10 could not be retrieved. After the full reports of the remaining 10 studies were read and additional data were obtained from the original investigators, 4 studies were excluded. The study performed by Barkemeyer et al26 compared a tapering-dosage regimen with pulse therapy with dexamethasone, using similar cumulative doses of dexamethasone in the 2 groups. Three other studies were excluded because the infants were subjected to individualized dosage regimens, which resulted in a broad range and often-overlapping cumulative dexamethasone doses in the 2 treatment arms.27–29
The remaining 6 studies met the inclusion criteria for this review, randomly assigning a total of 209 infants.20–25 Detailed descriptions of the included studies can be found in the Appendix. Five of the 6 original investigators provided the authors with additional data on methods, interventions, patient characteristics, or missing outcome parameters.20–24 The overall quality of 5 studies was fair to good (Table 1). There were insufficient data from the study by Ramanathan et al25 to allow a proper methodologic assessment.
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As shown in Table 2, most studies included preterm infants with comparable gestational age and birth weight, but there was considerable variation in the use of prenatal glucocorticoid and exogenous surfactant treatments. Dexamethasone administration was started in the moderately early period (7–14 days) in all trials except the study by Malloy et al,22 in which most infants received dexamethasone between the second week and the third week of life.
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The cumulative doses ranged from 0.6 to 3.0 mg/kg in the low-dosage regimens and from 1.9 to 7.9 mg/kg in the high-dosage regimens (Table 3). Two studies contrasted doses in the higher ranges20,21 and 4 studies in the lower ranges.22–25 Only 2 studies reported no late rescue treatment with dexamethasone in the 2 treatment groups (Table 3).
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Outcome Parameters
Death and CLD
Decreasing the cumulative dexamethasone dose had no significant effect on mortality rates at PMA of 36 weeks or at discharge in the high- and low-range subgroups (Table 4). In the subgroup of trials contrasting dexamethasone doses in the higher ranges, higher doses were more effective in reducing CLD rates than were lower doses (typical RR: 0.67; 95% CI: 0.45–0.99; number needed to treat: 4; 95% CI: 2–118). No differences in CLD rates were found in the subgroup of trials contrasting dexamethasone doses in the lower ranges. As shown in Fig 1, combining rates of CLD and death did not change these findings, showing a significant reduction only in the high-range subgroup (typical RR: 0.74; 95% CI: 0.55–1.00; number needed to treat: 4; 95% CI: 2–58).
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Neurodevelopmental Sequelae
Four studies reported long-term neurodevelopmental outcomes of the survivors, including 66% to 100% of the randomly assigned infants. Malloy et al22 also performed long-term neurodevelopmental assessments but used the modified Gesell Developmental Appraisal, which was deemed not to be comparable to the MDI values reported in the other studies (Table 1).
Subgroup analyses showed no significant differences in the incidence of cerebral palsy between the high- and low-dosage regimens (Table 4). Combining this outcome with death at hospital discharge did not change this finding (Table 4 and Fig 2). There were no significant differences between the subgroups with higher- and lower-dose dexamethasone treatment in the numbers of infants with MDI values of <2 SD or with visual impairment (Table 4).
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Short-Term Outcomes
In the high-range subgroup, using a higher dexamethasone dose did not significantly decrease the number of infants who experienced extubation failure at day 3 and day 7. In the low-range subgroups, fewer infants tended to experience extubation failure at day 3 and day 7, but this difference did not reach statistical significance (Table 4). The duration of mechanical ventilation was not significantly affected by the dexamethasone dose in the 2 subgroups. Short-term adverse effects of hypertension and hyperglycemia, but not sepsis, were more frequent in the group treated with the higher dexamethasone dose, compared with the lower dose, but this difference reached statistical significance only in the low-range subgroup (Table 4).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSAPPENDIX: DESCRIPTION OF...REFERENCES |
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Despite the firm recommendations of several pediatric societies to stop using postnatal systemic dexamethasone treatment outside the realm of RCTs and despite the fact that the optimal dexamethasone dose is not known, clinicians are still using dexamethasone to treat ventilator-dependent preterm infants.16–19 Attempts to identify the optimal cumulative dexamethasone dose are therefore clinically relevant and important. This systematic review summarizes all published studies that investigated whether a lower dexamethasone dose would be effective in reducing the incidence of CLD while decreasing the risk for adverse effects.
After data extraction, it became apparent that the absolute dexamethasone doses used to contrast higher-dosage and lower-dosage regimens varied considerably among the included trials. In fact, the higher-dosage regimen in 4 studies used a dexamethasone dose that was equal to or less than the lower-dosage regimen in the 2 other trials. No trial compared 2 dexamethasone regimens across the full range of the reported doses. Because of this heterogeneity in dose contrast, we thought that a pooled analysis of all 6 available trials would not be useful. Therefore, we divided the studies into high-range and low-range subgroups and analyzed the pooled data for these subgroups separately. We emphasize that the terms "high" and "low," as used to describe both the subgroups and the dexamethasone comparisons, should be interpreted from a relative perspective because, compared with physiologic levels of glucocorticoids, all reported doses are supraphysiologic (ie, high).
We found no effect of lower cumulative dexamethasone doses on mortality rates at either PMA of 36 weeks or discharge, compared with higher doses. This is consistent with previous meta-analyses comparing dexamethasone with placebo.10,11 In the high-range subgroup, however, the incidence of CLD was significantly lower in the infants treated with a higher versus lower dexamethasone dose. Combining the outcomes of CLD and death at PMA of 36 weeks did not change this finding, which indicates that the reduction in CLD in this subgroup was not caused by differences in mortality rates. This reduction in CLD in favor of the high-dosage regimen was not observed in the low-range subgroup. We can only speculate on the possible explanations for this finding. First, the number of CLD events was considerably higher in the studies contrasting dexamethasone in the higher dose ranges, compared with studies in the lower ranges, which suggests that there was heterogeneity in terms of higher a priori risks for CLD among children included in the trials of the 2 subgroups. Indeed, one of the studies in the high-range subgroup was performed in the presurfactant era, and another study in that subgroup included infants with quite low birth weight and gestational age.20,21 Both of these factors are known to increase the a priori risk for CLD. Second, the use of additional ("rescue") dexamethasone treatment outside the study protocol for infants in both arms of the trials was observed only in the studies in the low-range subgroup. This could have resulted in an underestimation of the true treatment effect in those trials. Finally, a relatively lower cumulative dexamethasone dose, as used in the low-range subgroup, might be insufficient, in a pharmacodynamic sense, to change the occurrence of CLD, and therefore any contrast in this low range would show no difference in CLD rates.
We found no differences in the occurrence of cerebral palsy alone or cerebral palsy combined with death with the high-dosage versus low-dosage regimens. Analysis of Bayley's MDI values and visual impairments showed comparable results. These results suggest that the changes in the dexamethasone doses do not affect the risk for neurodevelopmental sequelae, which is consistent with previous meta-analyses comparing dexamethasone administered moderately early with placebo.11 However, we think that these results on neurodevelopmental sequelae should be interpreted with caution, for the following reasons. First, the low a priori chance of adverse neurodevelopmental outcomes such as cerebral palsy and the relatively small number of infants included in this analysis might be insufficient for detection of clinically relevant treatment effects on these outcomes. Second, the number of infants lost to follow-up monitoring was >10% in 2 of the 3 studies, which might have biased the results, because we know that especially children with cerebral palsy are difficult to monitor.30 Third, and complicating matters, CLD was shown in another study to be an independent risk factor for cerebral palsy, which suggests that preventing CLD with dexamethasone in high-risk infants also could decrease the risk of cerebral palsy combined with death.31 On the basis of that report, it might well be that the increased risk for CLD with the lower-dosage regimen, as reported in this review, overrides a (possible) reduction in the incidence of neurodevelopmental sequelae with a lower dexamethasone dose.
Meta-analyses comparing dexamethasone with placebo showed that dexamethasone facilitated weaning and extubation from mechanical ventilation, expressed as failure to extubate 3 or 7 days after initiation of dexamethasone therapy. The present meta-analysis also showed that infants treated with the higher-dosage regimen of dexamethasone, compared with the lower-dosage regimen, tended to have a lower risk of experiencing extubation failure at day 3 and 7, but only in the low-range subgroup. The fact that we did not find this difference in the high-range subgroup could be explained by the fact that the studies in that subgroup used comparable starting doses (0.5 mg/kg) in the 2 treatment arms. This was in contrast to the studies in the low-range subgroup, which used starting doses of 0.4 to 0.5 mg/kg per day in the higher-dosage treatment arm and doses of 0.2 mg/kg per day in the lower-dosage treatment arm. This difference in starting dose could have affected the early pulmonary changes after initiation of dexamethasone treatment and thus the chances of successful extubation within the first week of treatment.
In line with previous results from a meta-analysis on moderately early dexamethasone use,11 we observed an increased risk for hyperglycemia and hypertension, but not sepsis, in the groups receiving the higher dexamethasone dose. This suggests that using lower dexamethasone doses might reduce short-term adverse effects. The relevance of this finding in relation to CLD and neurodevelopmental outcomes is questionable.
This meta-analysis has several limitations. First, as discussed earlier, the sample size of this analysis was small, which resulted in inadequate power to detect small but clinically relevant differences in some of the important outcome parameters. Second, although most studies contrasted 2 dosage regimens of dexamethasone, there was diversity in the study designs, such as the cumulative dexamethasone doses used in the 2 arms, the starting doses, and the duration of therapy. It remains unclear whether and how these differences affect the observed treatment effect of dexamethasone. Third, the use of late rescue glucocorticoid treatment outside the study protocol was considerable in the majority of the trials, and this might have confounded the true dexamethasone treatment effect. However, the fact that contamination was not present in the high-range subgroup indicates that the observed reduction in CLD rates in this subgroup in favor of the higher dexamethasone dose was indeed a dose-dependent treatment effect. Finally, not all studies reported neurodevelopmental outcome parameters, and those that did used various definitions or assessed the outcomes at different time points. Although we pooled the data as if they were homogeneous, this apparent clinical heterogeneity compromises the validity of the results of our meta-analysis.
This review demonstrates that the volume and quality of the currently available evidence are insufficient for determination of the optimal dose of systemically administered dexamethasone for the treatment of ventilator-dependent preterm infants at risk for CLD. Although this review suggests that a reduction in dexamethasone dose might increase the incidence of CLD without decreasing the risk for adverse neurodevelopmental outcomes, the validity of this observation is compromised by the presence of several confounding factors.
Therefore, we conclude that a large multicenter study comparing a higher cumulative dexamethasone dose with a lower dose, using comparable durations of treatment, is urgently needed. The clinical community should decide whether there is still room for a placebo arm in such a trial. Although the current evidence prevents firm recommendations, this review suggests contrasting dexamethasone doses in higher ranges. Such a trial should be adequately powered to detect small but clinically relevant treatment effects. Therefore, it should include ventilated preterm infants with a high risk for CLD, on the basis of known determinants in the development of CLD. The time to initiate dexamethasone treatment should be predefined, and administration should start between 7 and 14 days after birth, considering the (negative) results from previous meta-analysis on early and delayed use.9,10 One of the challenges will be to identify infants with a high risk for CLD and/or neurodevelopmental sequelae in the second week of life. We recommend that data on the following primary outcome parameters be collected in any future comparative study: CLD at PMA of 36 weeks, death at PMA of 36 weeks and at discharge, and neurodevelopmental outcomes, using predefined definitions, diagnostic tests, and time points. In addition, short-term benefits (time of extubation and ventilation time) and adverse effects (hypertension, sepsis, and hyperglycemia) could be reported as secondary outcomes. Various threats to validity should be recognized. For example, dilution of treatment effects attributable to the use of glucocorticoids outside the study protocol, or crossing over between trial arms, should be avoided as much as possible. In any event, additional treatments should be reported adequately, for assessment of the possibility of confounding.
Although major pediatric societies have indicated that more studies on dexamethasone use in preterm infants at risk for CLD are urgently needed, attempts to recruit patients for a RCT of low-dose dexamethasone failed.32 It was suggested that the apparent reluctance to participate in a RCT on dexamethasone use in preterm infants was caused by ongoing concerns about adverse neurologic sequelae. However, this increased risk for death or adverse neurodevelopmental outcomes was reported only in RCTs exploring early dexamethasone treatment.9 In light of the ongoing use of dexamethasone in clinical settings, we think that a future RCT on dexamethasone dosages is justified and is urgently needed. Awaiting such a trial, we recommend that dexamethasone not be administered outside the published guidelines of the pediatric societies.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSAPPENDIX: DESCRIPTION OF...REFERENCES |
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The present meta-analysis shows that all studies performed to date that compared high and low dexamethasone dosage regimens in preterm infants at risk for CLD randomly assigned small numbers of patients. They differed considerably in the cumulative dexamethasone dose, cointerventions, and neurodevelopmental outcomes measured. Given these limitations, the present review cannot determine the optimal dexamethasone dose. A large multicenter RCT is urgently needed to provide more-conclusive evidence on what the optimal dexamethasone dose should be.
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APPENDIX: DESCRIPTION OF INCLUDED STUDIES |
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The double-blind, placebo-controlled RCT performed by Cummings et al20 included 36 preterm infants with birth weights of
1250 g, gestational ages of 30 weeks, and postnatal ages of >14 days. All infants underwent ventilation at a rate of 15 cycles per minute and received >30% oxygen. Attempts to wean these settings failed over a period of 72 hours. Infants with a symptomatic patent ductus arteriosus, renal failure, or sepsis at entry were excluded. The included infants were randomly assigned to 1 of 3 dosage regimens, that is, (1) a high-dosage regimen with a cumulative dose of 7.9 mg/kg dexamethasone administered over a 42-day course with 0.5 mg/kg per day for 3 days, 0.3 mg/kg per day for 3 days, a 10% decrease every 3 days until 0.1 mg/kg per day, 0.1 mg/kg per day for 3 days, and 0.1 mg/kg per day on alternate days for 7 days; (2) a low-dosage regimen with a cumulative dose of 3 mg/kg administered over 18 days with 0.5 mg/kg per day for 3 days, a 50% decrease every 3 days until 0.06 mg/kg per day, 0.06 mg/kg per day for 3 days, and 0.06 mg/kg per day on alternate days for 7 days; or (3) saline placebo. Medication was administered intravenously and divided into 2 doses per day. Each infant received the same volume of medication through the use of different concentrations of dexamethasone. Infants in the low-dosage regimen group received additional saline injections to complete the 42-day course. The placebo group was excluded for the purpose of this review. No glucocorticoid treatment outside the protocol was allowed. The primary outcomes were death, duration of mechanical ventilation, and duration of oxygen dependence. Secondary outcomes were duration of hospitalization, occurrence of retinopathy of prematurity, occurrence of bloody gastric aspirates, number of transfusions, and occurrence of clinically suspected sepsis, hypertension, hyperglycemia, and hypertriglyceridemia. Growth and neurodevelopment (abnormal neurologic outcomes and Bayley Scales of Infant Development scores) were assessed at 6 and 15 months of age, corrected for prematurity, by examiners blinded to the treatments. Normal neurodevelopmental outcomes were defined as having Bayley's MDI and Psychomotor Developmental Index values of >84 and normal neurologic findings (not specified). The original investigators provided additional data on the duration of mechanical ventilation, failure to extubate on day 7, and the total number of patients with Bayley's MDI scores of <2 SD. DeMartini and Muraskas21 included 30 intubated preterm newborns in a RCT to compare a 7-day pulse course and a 21-day tapered course of dexamethasone. The infants were randomly assigned to 1 of 2 dosage regimens, that is, (1) a high-dosage regimen with a cumulative dose of 4.1 mg/kg dexamethasone administered over a 21-day course with 0.5 mg/kg per day for 2 days, 0.3 mg/kg per day for 3 days, 0.24 mg/kg per day for 3 days, 0.2 mg/kg per day for 3 days, 0.14 mg/kg per day for 3 days, 0.1 mg/kg per day for 3 days, and then 2 doses of 0.1 mg/kg every 48 hours; or (2) low-dosage regimen with a cumulative dose of 2.7 mg/kg dexamethasone administered over a 7-day course with 0.5 mg/kg per day for 3 days and then 0.3 mg/kg per day for 4 days. All medication was divided into 2 doses per day. No patients were treated with any glucocorticoids outside the study protocol. The primary outcomes were death, duration of mechanical ventilation, and duration of oxygen dependence. Secondary outcomes were the occurrence of clinically suspected sepsis, necrotizing enterocolitis, hypertension, hyperglycemia, and hypertriglyceridemia. No long-term follow-up monitoring was performed. The original investigators provided data concerning the incidence of CLD (defined as oxygen dependence at PMA of 36 weeks) combined with death at 36 weeks.
The prospective RCT performed by Durand et al23 was designed to compare the effects of 2 dexamethasone dosage schedules on dynamic pulmonary mechanics, ventilator settings, and oxygen dependence in 47 ventilated preterm neonates. Infants were included if they had a birth weight between 501 and 1500 g, a gestational age between 24 and 32 weeks, and a postnatal age between 7 and 14 days and at entry required ventilatory support with a rate of 15 cycles per minute and 30% supplemental oxygen to maintain a pulse oxygen saturation of 90%, despite weaning trials. Infants were excluded from the randomization if they had multiple congenital anomalies or chromosomal abnormalities, systemic hypertension, congenital heart disease, intraventricular hemorrhage grade IV, renal failure, or sepsis at entry. The included infants were randomly assigned to 1 of 2 dosage regimens, that is, (1) a high-dosage regimen with a cumulative dose of 2.4 mg/kg dexamethasone administered over a 7-day course with 0.5 mg/kg per day for 3 days, 0.25 mg/kg per day for 3 days, and then 0.1 mg/kg per day for 1 day; or (2) a low-dosage regimen with a cumulative dose of 1.0 mg/kg dexamethasone administered over a 7 day course with 0.2 mg/kg per day for 3 days and then 0.1 mg/kg per day for 4 days. All medication was divided into 2 doses per day. Administration of open-label dexamethasone was allowed after the study period, at the discretion of the attending neonatologist. The primary outcomes were the dynamic respiratory mechanics, measured before and on day 2, 5, and 7 of dexamethasone therapy. Secondary outcomes were ventilator settings, occurrence of CLD (defined as oxygen dependence at PMA of 36 weeks), survival without CLD, duration of mechanical ventilation, duration of hospitalization, and occurrence of hyperglycemia, hypertension, retinopathy of prematurity, necrotizing enterocolitis, spontaneous gastrointestinal perforation, sepsis, and pulmonary air leaks. Long-term follow-up data were retrieved from the original investigators.
McEvoy et al24 investigated the effects of 2 dexamethasone dosage schedules on functional residual capacity and passive respiratory compliance in 26 preterm infants. Infants were included when they were between 7 and 21 days of postnatal age, with birth weights of >501 g and <1500 g and gestational ages of >24 weeks and <32 weeks. The infants were dependent on ventilatory support with 15 cycles per minute and oxygen levels of 30% at entry. Infants with multiple congenital anomalies, systemic hypertension, congenital heart disease, intraventricular hemorrhage grade IV, renal failure, or sepsis at entry were excluded. The included infants were randomly assigned to 1 of 2 dosage regimens, that is, (1) a high-dosage regimen with a cumulative dose of 2.4 mg/kg dexamethasone administered over a 7-day course with 0.5 mg/kg per day for 3 days, 0.25 mg/kg per day for 3 days, and then 0.1 mg/kg per day for 1 day; or (2) a low-dosage regimen with a cumulative dose of 1.0 mg/kg dexamethasone administered over a 7-day course with 0.2 mg/kg per day for 3 days and then 0.1 mg/kg per day for 4 days. All medication was divided into 2 doses per day. The use of open-label dexamethasone was discouraged, but it could be administered at the discretion of the attending neonatologist. The primary outcomes were functional residual capacity and passive respiratory compliance before and during the 7-day therapy. Secondary outcomes were ventilator settings, duration of mechanical ventilation, duration of hospitalization, occurrence of CLD (defined as oxygen dependence at PMA of 36 weeks), survival without CLD, and occurrence of patent ductus arteriosus, hyperglycemia, hypertension, intraventricular hemorrhage, periventricular leukomalacia, retinopathy of prematurity, necrotizing enterocolitis, spontaneous gastrointestinal perforation, sepsis, and pulmonary air leaks. At corrected age of 1 year, the infants underwent early neurodevelopmental follow-up assessments (cerebral palsy evaluation and the Bayley Scales of Infant Development) by a developmental pediatrician, a pediatric neurologist, and specialized personnel. Cerebral palsy was defined as nonprogressive motor impairment characterized by abnormal muscle tone and decreased range/control of movements. Severe cognitive delay was defined as MDI scores of <70. Additional data on duration of mechanical ventilation and failure to extubate on days 3 and 7 were retrieved from the original investigators.
The prospective RCT performed by Ramanathan et al25 included 28 infants with birth weights between 520 and 1440 g and gestational ages of 27 weeks. The included infants were randomly assigned at 10 to 14 days of age to 1 of 2 dosage regimens, that is, (1) a high-dosage schedule with an estimated cumulative dose of 1.9 mg/kg dexamethasone administered over a 7-day course with 0.4 mg/kg per day for 2 days and tapering for the subsequent 5 days; or (2) a low-dosage regimen with an estimated cumulative dose of 1.0 mg/kg administered over a 7-day course with 0.2 mg/kg for 2 days and then tapering for the subsequent 5 days. Clinical outcomes were death at discharge, duration of mechanical ventilation and oxygen dependence, survival without CLD, retreatment with dexamethasone, and occurrence of retinopathy of prematurity of stage II or greater, sepsis, and hyperglycemia. No long-term follow-up data were reported, and no additional data were retrieved.
The prospective, double-blind RCT performed by Malloy et al22 included 17 infants with birth weights of <1500 g and gestational age of 34 weeks. The included infants were randomly assigned before day 28 of age to 1 of 2 dosage regimens, that is, (1) a high-dosage schedule with a cumulative dose of 2.7 mg/kg dexamethasone administered over a 7-day course with 0.5 mg/kg per day for 3 days followed by 0.3 mg/kg for 4 days; or (2) a low-dosage regimen with a cumulative dose of 0.56 mg/kg administered over a 7-day course with 0.08 mg/kg for 7 days. This study was terminated prematurely because of the 2002 statement from the American Academy of Pediatrics and the Canadian Paediatric Society.14 Clinical outcomes for the patients already enrolled were death at discharge, duration of mechanical ventilation and oxygen dependence, survival without CLD, retreatment with dexamethasone, number of days with oxygen supplementation, number of hospital days, and occurrence of intraventricular hemorrhage, necrotizing enterocolitis, gastrointestinal perforation, retinopathy of prematurity requiring laser photocoagulation, hypertension, and hyperglycemia. Long-term follow-up monitoring was performed through 3 years of age, and neurodevelopmental status was assessed by using the modified Gesell Developmental Appraisal. Additional data on failure to extubate on day 3, mechanical ventilation, and blindness or poor vision were retrieved from the original investigators.
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ACKNOWLEDGMENTS |
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We thank Dr J. K. Muraskas, Loyola University Medical Center, Dr M. Durand, Los Angeles County-University of Southern California Medical Center, Dr C. McEvoy, Oregon Health Sciences University, Dr C. A. Malloy, Children's Memorial Hospital, Northwestern University Feinberg School of Medicine, and Dr J. J. Cummings, Brody School of Medicine, East Carolina University, for providing us with additional data and thoughtful review of the manuscript.
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FOOTNOTES |
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Accepted Oct 31, 2007.
Address correspondence to Anton H. van Kaam, MD, PhD, Department of Neonatology (Room H3-150), Emma Children's Hospital AMC, PO Box 22700, 1100 DD Amsterdam, Netherlands. E-mail: a.h.vankaam{at}amc.uva.nl
The authors have indicated they have no financial relationships relevant to this article to disclose.
| What's Known on This Subject Systemic postnatal dexamethasone treatment reduces the risk of chronic lung disease in preterm infants but may be associated with dose-related increased risk of neurodevelopmental impairment. Despite the wide use of dexamethasone, its optimal dose is not known.
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| What This Study Adds This systematic review of trials comparing higher versus lower cumulative dexamethasone doses shows that the volume and quality of the available evidence are insufficient for determination of the optimal dose. Well-designed studies are urgently needed.
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PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics
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