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Effects of Higher Versus Lower Dexamethasone Doses on Pulmonary and Neurodevelopmental Sequelae in Preterm Infants at Risk for Chronic Lung Disease: A Meta-analysis

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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

Wes Onland, MDa, Anne P. De Jaegere, MDa, Martin Offringa, MD, PhDa,b, Anton H. van Kaam, MD, PhDa

aDepartment of Neonatology andbCenter for Pediatric Clinical Epidemiology, Emma Children’s Hospital, Academic Medical Center, University of Amsterdam,

Amsterdam, Netherlands

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 neurodevel-opmental impairment. Despite the wide use of dexamethasone, its optimal dose is not known.

What This Study Adds

This systematic review of trials comparing higher versus lower cumulative dexametha-sone 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.

ABSTRACT

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 neurodevelop-mental outcomes, in preterm infants.

METHODS.Randomized, controlled trials comparing higher- versus lower-dosage dexa-methasone 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 out-comes 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 (ⱕ2.7 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.Pediatrics2008;122:92–101

C

HRONIC 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.3–5Since 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.6Others used glucocorticoid therapy for infants who had

www.pediatrics.org/cgi/doi/10.1542/ peds.2007-2258

doi:10.1542/peds.2007-2258

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

Accepted for publication 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@amc.uva.nl

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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 dexameth-asone, 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 post-natal administration.9–11At the end of the 1990s,

how-ever, the first reports of long-term neurodevelopmental outcomes were published, showing that postnatal sys-temic dexamethasone treatment was associated with in-creased risk of abnormal neurologic development.12,13In

response to those reports, the American Academy of Pediatrics, the Canadian Paediatric Society, and the Eu-ropean Association of Perinatal Medicine concluded that routine use of systemic dexamethasone for the treat-ment 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

deter-mine 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.20–25Given the small number of patients

in-cluded in those individual RCTs, we conin-cluded 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.

METHODS

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 “ste-roid,” “glucocorticoid,” and “dexamethasone.” Previous re-view 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 reg-imen of systemic dexamethasone treatment, compared with a lower-dosage regimen. Studies using different types of glucocorticoids (hydrocortisone and methylpredniso-lone) or inhalation glucocorticoids were excluded because a direct dose comparison of these steroids and administra-tion routes with intravenous dexamethasone doses is not possible. (3) The studies reportedⱖ1 of the following out-come parameters: death, CLD, or long-term neurodevelop-mental 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,

com-pleteness of follow-up monitoring, and blinding of out-come 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; dexa-methasone 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 glu-cocorticoids outside the study period; death at PMA of 36 weeks and/or at hospital discharge; CLD, defined as ox-ygen dependence at PMA of 36 weeks; incidence rates of hypertension, sepsis, and hyperglycemia during hospi-talization; 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 dexa-methasone 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. Stud-ies were assigned to the high-range subgroup if the cumu-lative dexamethasone dose used in the higher dosage reg-imen was⬎2.7 mg/kg and to the low-range subgroup if the cumulative dose used in the higher dosage regimen was

ⱕ2.7 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 Collab-oration 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.

RESULTS

Study Characteristics

A total of 11 articles were identified by using the afore-mentioned search strategy. The unpublished article by Ariagno and colleagues reported in the Cochrane review by Halliday et al10could not be retrieved. After the full

reports of the remaining 10 studies were read and addi-tional data were obtained from the original investigators, 4 studies were excluded. The study performed by Barke-meyer et al26compared a tapering-dosage regimen with

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subjected to individualized dosage regimens, which re-sulted in a broad range and often-overlapping cumula-tive 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 in-fants.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.20–24The overall quality of 5

studies was fair to good (Table 1). There were insuffi-cient data from the study by Ramanathan et al25to allow

a proper methodologic assessment.

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,22in which most infants

received dexamethasone between the second week and the third week of life.

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 con-trasted doses in the higher ranges20,21and 4 studies in the

lower ranges.22–25Only 2 studies reported no late rescue

treatment with dexamethasone in the 2 treatment groups (Table 3).

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 effec-tive 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 (typ-ical RR: 0.74; 95% CI: 0.55–1.00; number needed to treat: 4; 95% CI: 2–58).

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

per-TABLE 1 Methods of Included Studies

Randomization Concealment of Allocation

Blinding of Intervention

Completeness of Follow-up Monitoring,

% (n/N)

Blinding of Assessment

Cummings et al20 Yes Adequate Yes 100 (18/18) Yes

DeMartini and Muraskas21 Yes Adequate Yes No follow-up monitoring Yes

Malloy et al22 Yes Adequate Yes 93 (14/15) Yes

Durand et al23 Yes Adequate No 80 (36/45) No

McEvoy et al24 Yes Adequate Yes 66 (39/59) Yes

Ramanathan et al25 Yes Insufficient data Insufficient data Insufficient data Insufficient data

TABLE 2 Patient Characteristics in Included Studies

Group No. of

Patients

Birth Weight, Mean⫾SD, g

Gestational Age, Mean⫾SD, wk

Prenatal Steroid Treatment, %

Surfactant Treatment, %

Cummings et al20

High 13 818⫾145 26.0⫾2.0 38 0

Low 12 810⫾208 26.0⫾2.0 25 0

DeMartini and Muraskas21

High 16 741⫾142 25.5⫾1.7 62 100

Low 14 848⫾224 26.4⫾1.6 64 100

Malloy et al22

High 9a 767149 25.80.9 75 100

Low 8 773⫾182 26.1⫾1.8 63 100

Durand et al23

High 23 932⫾182 27.1⫾1.8 52 87

Low 24 858⫾186 26.9⫾1.6 50 88

McEvoy et al24

High 29 839⫾229 26.1⫾2.0 34 97

Low 33 830⫾248 26.3⫾1.8 48 82

Ramanathan et al25

High 15 850⫾290 27.0⫾2.0 ? 67

Low 13 817⫾186 27.0⫾2.0 ? 62

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formed 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 impair-ment (Table 4).

Short-Term Outcomes

In the high-range subgroup, using a higher dexametha-sone 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 sig-nificantly 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).

DISCUSSION

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 ventila-tor-dependent preterm infants.16–19 Attempts to identify

the optimal cumulative dexamethasone dose are there-fore clinically relevant and important. This systematic review summarizes all published studies that investi-gated whether a lower dexamethasone dose would be effective in reducing the incidence of CLD while decreas-ing the risk for adverse effects.

After data extraction, it became apparent that the absolute dexamethasone doses used to contrast higher-dosage and lower-higher-dosage regimens varied considerably among the included trials. In fact, the higher-dosage regimen in 4 studies used a dexamethasone dose that

TABLE 4 Primary and Secondary Outcomes

Outcome High-Range Contrast Low-Range Contrast

No. of Studiesa

High Dose,

n/N

Low Dose,

n/N

Typical RR (95% CI) No. of Studiesa

High Dose,

n/N

Low Dose,

n/N

Typical RR (95% CI)

Death at PMA of 36 wk 2 4/29 3/26 1.23 (0.34–4.40) 4 6/76 2/78 2.32 (0.62–8.76) Death at hospital discharge 2 8/29 8/26 0.90 (0.39–2.05) 4 6/76 2/78 2.32 (0.62–8.76)

CLD 2 15/29 20/26 0.67 (0.45–0.99) 4 15/76 17/78 0.89 (0.51–1.55)

Combined death and CLD 2 19/29 23/26 0.74 (0.55–1.00) 4 21/76 20/78 1.06 (0.66–1.70)

CP 1 0/9 5/9 0.09 (0.01–1.44) 2 4/39 4/36 0.93 (0.25–3.43)

Combined death and CP 1 4/13 8/12 0.46 (0.19–1.14) 2 7/52 6/57 1.28 (0.46–3.54) Bayley’s MDI score of⬍2 SD 1 0/9 5/9 0.09 (0.01–1.44) 2 9/39 6/36 1.38 (0.55–3.50)

Blindness or poor vision 1 0/9 0/9 NE 2 3/47 0/42 2.63 (0.44–55.77)

Late rescue steroid treatment 2 0/29 0/26 NE 4 38/76 31/78 1.24 (0.88–1.74)

Failure to extubate on day 3 1 11/13 10/12 1.02 (0.72–1.43) 3 43/61 52/65 0.88 (0.72–1.08) Failure to extubate on day 7 1 9/13 9/12 0.92 (0.57–1.50) 3 37/61 47/65 0.84 (0.65–1.09) Duration of mechanical ventilation 2 29 26 ⫺1.67 (⫺11.31 to 7.96) 3 53 54 ⫺2.03 (⫺9.20 to 5.15) Hypertension (⬎2 SD) 2 2/29 0/26 4.41 (0.23–84.79) 3 13/61 4/65 3.18 (1.15–8.83) Hyperglycemia (⬎150 mg/dL) 2 15/29 11/26 1.21 (0.69–2.15) 3 15/61 6/65 2.50 (1.07–5.83) Sepsis (culture proven) 2 10/29 11/26 0.82 (0.41–1.61) 3 11/67 11/70 0.91 (0.55–1.51)

NE indicates not estimable; CP, cerebral palsy. High-range contrast indicates trials using cumulative dexamethasone doses in the higher ranges (⬎2.7 mg/kg in the higher-dosage regimen). Low-range contrast indicates trials using cumulative dexamethasone doses in the lower ranges (ⱕ2.7 mg/kg in the higher-dosage regimen).

aNumber of studies providing data.

TABLE 3 Dexamethasone Courses Used in Included Studies

Group Starting Dose, mg/kg

per d

Cumulative Dose, mg/kg

Total Duration of

Therapy, d

Late Rescue Treatment With Glucocorticoids,

%

Cummings et al20

High 0.5 7.9 42 0

Low 0.5 3.0 18 0

DeMartini and Muraskas21

High 0.5 4.1 21 0

Low 0.5 2.7 7 0

Malloy et al22

High 0.5 2.7 7 88

Low 0.08 0.6 7 50

Durand et al23

High 0.5 2.4 7 22

Low 0.2 1.0 7 29

McEvoy et al24

High 0.5 2.4 7 55

Low 0.2 1.0 7 39

Ramanathan et al25

High 0.4 1.9a 7 67

Low 0.2 1.0a 7 54

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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 em-phasize that the terms “high” and “low,” as used to describe both the subgroups and the dexamethasone comparisons, should be interpreted from a relative per-spective because, compared with physiologic levels of glucocorticoids, all reported doses are supraphysiologic (ie, high).

We found no effect of lower cumulative dexametha-sone doses on mortality rates at either PMA of 36 weeks or discharge, compared with higher doses. This is

con-sistent with previous meta-analyses comparing dexa-methasone with placebo.10,11 In the high-range

sub-group, 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 con-siderably higher in the studies contrasting dexametha-sone in the higher dose ranges, compared with studies in the lower ranges, which suggests that there was heter-ogeneity in terms of higher a priori risks for CLD among children included in the trials of the 2 subgroups. In-FIGURE 1

Meta-analysis of the combined outcome of death and CLD at PMA of 36 weeks. High-range contrast indicates trials using cumulative dexamethasone doses in the higher ranges (⬎2.7 mg/kg in the higher-dosage regimen). Low-range contrast in-dicates trials using cumulative dexamethasone doses in the lower ranges (ⱕ2.7 mg/kg in the higher-dosage regimen) Each dot is RR of 1 study. The size of the shaded square indi-cates the weight of the study in the meta-analysis. The hori-zontal line indicates the 95% CI. The diamond indicates the subtotal of the studies shown above (meta-analysis), the cen-ter being the typical RR and the distance between the ex-tremes (left and right) being the 95% CI. The arrow in the study by Ramanathan et al25indicates that the 95% CI exceeds the

scaling of the RR shown at the bottom. The vertical line indi-cates a RR of 1 (no difference).

FIGURE 2

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deed, 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.20,21Both 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 underestima-tion 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 consis-tent with previous meta-analyses comparing dexameth-asone administered moderately early with placebo.11

However, we think that these results on neurodevelop-mental 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 moni-toring was⬎10% in 2 of the 3 studies, which might have biased the results, because we know that especially chil-dren with cerebral palsy are difficult to monitor.30Third,

and complicating matters, CLD was shown in another study to be an independent risk factor for cerebral palsy, which suggests that preventing CLD with dexametha-sone 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 dexa-methasone dose.

Meta-analyses comparing dexamethasone with pla-cebo 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 reg-imen of dexamethasone, compared with the lower-dos-age 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 dif-ference in the high-range subgroup could be explained by the fact that the studies in that subgroup used com-parable 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

ⱕ0.2 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 dexametha-sone treatment and thus the chances of successful extu-bation within the first week of treatment.

In line with previous results from a meta-analysis on moderately early dexamethasone use,11we observed an

increased risk for hyperglycemia and hypertension, but not sepsis, in the groups receiving the higher dexameth-asone dose. This suggests that using lower dexametha-sone doses might reduce short-term adverse effects. The relevance of this finding in relation to CLD and neuro-developmental 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 re-mains 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 dexameth-asone treatment effect. However, the fact that contamina-tion 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 ad-ministered dexamethasone for the treatment of ventila-tor-dependent preterm infants at risk for CLD. Although this review suggests that a reduction in dexamethasone dose might increase the incidence of CLD without de-creasing the risk for adverse neurodevelopmental out-comes, the validity of this observation is compromised by the presence of several confounding factors.

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treatment should be predefined, and administration should start between 7 and 14 days after birth, consid-ering the (negative) results from previous meta-analysis on early and delayed use.9,10One 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 out-come 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 out-comes, 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 re-ported as secondary outcomes. Various threats to valid-ity should be recognized. For example, dilution of treat-ment 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 ade-quately, 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.32It

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 ad-verse neurodevelopmental outcomes was reported only in RCTs exploring early dexamethasone treatment.9In

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.

CONCLUSIONS

The present meta-analysis shows that all studies per-formed to date that compared high and low dexameth-asone dosage regimens in preterm infants at risk for CLD randomly assigned small numbers of patients. They dif-fered considerably in the cumulative dexamethasone dose, cointerventions, and neurodevelopmental out-comes 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.

APPENDIX: DESCRIPTION OF INCLUDED STUDIES

The double-blind, placebo-controlled RCT performed by Cummings et al20included 36 preterm infants with birth

weights ofⱕ1250 g, gestational ages ofⱕ30 weeks, and postnatal ages of⬎14 days. All infants underwent ven-tilation at a rate ofⱖ15 cycles per minute and received

⬎30% oxygen. Attempts to wean these settings failed over a period ofⱖ72 hours. Infants with a symptomatic patent ductus arteriosus, renal failure, or sepsis at entry

were excluded. The included infants were randomly as-signed 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 admin-istered intravenously and divided into 2 doses per day. Each infant received the same volume of medication through the use of different concentrations of dexa-methasone. 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 out-side the protocol was allowed. The primary outcomes were death, duration of mechanical ventilation, and du-ration 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 sus-pected sepsis, hypertension, hyperglycemia, and hyper-triglyceridemia. Growth and neurodevelopment (abnor-mal 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 out-comes were defined as having Bayley’s MDI and Psy-chomotor Developmental Index values of⬎84 and nor-mal 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 Muraskas21included 30 intubated

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orig-inal 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 al23was

designed to compare the effects of 2 dexamethasone dosage schedules on dynamic pulmonary mechanics, ventilator settings, and oxygen dependence in 47 venti-lated preterm neonates. Infants were included if they had a birth weight between 501 and 1500 g, a gesta-tional age between 24 and 32 weeks, and a postnatal age between 7 and 14 days and at entry required ventilatory support with a rate ofⱖ15 cycles per minute andⱖ30% supplemental oxygen to maintain a pulse oxygen satu-ration of ⱖ90%, despite weaning trials. Infants were excluded from the randomization if they had multiple congenital anomalies or chromosomal abnormalities, systemic hypertension, congenital heart disease, intra-ventricular 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 regi-men with a cumulative dose of 2.4 mg/kg dexametha-sone 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 dexameth-asone 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. Admin-istration of open-label dexamethasone was allowed after the study period, at the discretion of the attending neo-natologist. The primary outcomes were the dynamic res-piratory 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 with-out CLD, duration of mechanical ventilation, duration of hospitalization, and occurrence of hyperglycemia, hy-pertension, retinopathy of prematurity, necrotizing en-terocolitis, spontaneous gastrointestinal perforation, sepsis, and pulmonary air leaks. Long-term follow-up data were retrieved from the original investigators.

McEvoy et al24investigated the effects of 2

dexameth-asone dosage schedules on functional residual capacity and passive respiratory compliance in 26 preterm in-fants. 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 withⱖ15 cycles per minute and oxygen levels of

ⱖ30% at entry. Infants with multiple congenital anom-alies, 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 discre-tion of the attending neonatologist. The primary out-comes were functional residual capacity and passive re-spiratory compliance before and during the 7-day therapy. Secondary outcomes were ventilator settings, duration of mechanical ventilation, duration of hospital-ization, occurrence of CLD (defined as oxygen depen-dence at PMA of 36 weeks), survival without CLD, and occurrence of patent ductus arteriosus, hyperglycemia, hypertension, intraventricular hemorrhage, periven-tricular leukomalacia, retinopathy of prematurity, ne-crotizing enterocolitis, spontaneous gastrointestinal per-foration, sepsis, and pulmonary air leaks. At corrected age of 1 year, the infants underwent early neurodevel-opmental follow-up assessments (cerebral palsy evalua-tion 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 ab-normal muscle tone and decreased range/control of movements. Severe cognitive delay was defined as MDI scores of⬍70. Additional data on duration of mechani-cal ventilation and failure to extubate on days 3 and 7 were retrieved from the original investigators.

The prospective RCT performed by Ramanathan et al25included 28 infants with birth weights between 520

and 1440 g and gestational ages of 27 weeks. The in-cluded 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 admin-istered 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 mechan-ical ventilation and oxygen dependence, survival with-out CLD, retreatment with dexamethasone, and occur-rence 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 al22included 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 sched-ule 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 prema-turely because of the 2002 statement from the American Academy of Pediatrics and the Canadian Paediatric So-ciety.14 Clinical outcomes for the patients already

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with oxygen supplementation, number of hospital days, and occurrence of intraventricular hemorrhage, necro-tizing enterocolitis, gastrointestinal perforation, retinop-athy 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 venti-lation, and blindness or poor vision were retrieved from the original investigators.

ACKNOWLEDGMENTS

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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2. Hentschel J, Berger TM, Tschopp A, Muller M, Adams M, Bucher HU. Population-based study of bronchopulmonary dys-plasia in very low birth weight infants in Switzerland. Eur J Pediatr.2005;164(5):292–297

3. Carlton DP, Albertine KH, Cho SC, Lont M, Bland RD. Role of neutrophils in lung vascular injury and edema after premature birth in lambs.J Appl Physiol.1997;83(4):1307–1317

4. Ferreira PJ, Bunch TJ, Albertine KH, Carlton DP. Circulating neutrophil concentration and respiratory distress in premature infants.J Pediatr.2000;136(4):466 – 472

5. Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med.2001;163(7):1723–1729

6. Yeh TF, Lin YJ, Hsieh WS, et al. Early postnatal dexamethasone therapy for the prevention of chronic lung disease in preterm infants with respiratory distress syndrome: a multicenter clin-ical trial.Pediatrics.1997;100(4). Available at: www.pediatrics. org/cgi/content/full/100/4/e3

7. Durand M, Sardesai S, McEvoy C. Effects of early dexametha-sone therapy on pulmonary mechanics and chronic lung dis-ease in very low birth weight infants: a randomized, controlled trial.Pediatrics.1995;95(4):584 –590

8. Collaborative Dexamethasone Trial Group. Dexamethasone therapy in neonatal chronic lung disease: an international pla-cebo-controlled trial.Pediatrics.1991;88(3):421– 427

9. Halliday HL, Ehrenkranz RA, Doyle LW. Early postnatal (⬍96 hours) corticosteroids for preventing chronic lung disease in preterm infants.Cochrane Database Syst Rev.2003;(1):CD001146 10. Halliday HL, Ehrenkranz RA, Doyle LW. Delayed (⬎3 weeks) postnatal corticosteroids for chronic lung disease in preterm infants.Cochrane Database Syst Rev.2003;(1):CD001145 11. Halliday HL, Ehrenkranz RA, Doyle LW. Moderately early

(7–14 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database Syst Rev. 2003;(1):CD001144

12. Yeh TF, Lin YJ, Huang CC, et al. Early dexamethasone therapy

in preterm infants: a follow-up study.Pediatrics.1998;101(5). Available at: www.pediatrics.org/cgi/content/full/101/5/e7 13. O’Shea TM, Kothadia JM, Klinepeter KL, et al. Randomized

placebo-controlled trial of a 42-day tapering course of dexa-methasone to reduce the duration of ventilator dependency in very low birth weight infants: outcome of study participants at 1-year adjusted age.Pediatrics.1999;104(1):15–21

14. American Academy of Pediatrics, Committee on Fetus and Newborn, Canadian Paediatric Society, Fetus and Newborn Committee. Postnatal corticosteroids to treat or prevent chronic lung disease in preterm infants.Pediatrics.2002;109(2): 330 –338

15. Halliday HL. Guidelines on neonatal steroids. Prenat Neonat Med.2001;6(6):371–373

16. Shinwell ES, Lerner-Geva L, Lusky A, Reichman B. Less post-natal steroids, more bronchopulmonary dysplasia: a popula-tion-based study in very low birthweight infants.Arch Dis Child Fetal Neonatal Ed.2007;92(1):F30 –F33

17. Shinwell ES, Karplus M, Bader D, et al. Neonatologists are using much less dexamethasone.Arch Dis Child Fetal Neonatal Ed.2003;88(5):F432–F433

18. Walsh MC, Yao Q, Horbar JD, Carpenter JH, Lee SK, Ohlsson A. Changes in the use of postnatal steroids for bronchopulmo-nary dysplasia in 3 large neonatal networks.Pediatrics.2006; 118(5). Available at: www.pediatrics.org/cgi/content/full/118/ 5/e1328

19. Kaempf JW, Campbell B, Sklar RS, et al. Implementing poten-tially better practices to improve neonatal outcomes after re-ducing postnatal dexamethasone use in infants born between 501 and 1250 grams. Pediatrics. 2003;111(4). Available at: www.pediatrics.org/cgi/content/full/111/4/e534

20. Cummings JJ, D’Eugenio DB, Gross SJ. A controlled trial of dexamethasone in preterm infants at high risk for bronchopul-monary dysplasia.N Engl J Med.1989;320(23):1505–1510 21. DeMartini TJ, Muraskas JK. Pulse versus tapered dosing

dexa-methasone for evolving bronchopulmonary dysplasia (BPD). Pediatr Res.1999;45(4):300A

22. Malloy CA, Hilal K, Weiss MG, Rizvi Z, Muraskas JK. A prospec-tive, randomized, double-masked trial comparing low dose to conventional dose dexamethasone in neonatal chronic lung dis-ease.Internet J Pediatr Neonatol.2005;5(1). Available at: http://216. 39.195.236/ostia/index.php?xmlFilePath⫽journals/ijpn/vol5n1/ dexamethasone.xml

23. Durand M, Mendoza ME, Tantivit P, Kugelman A, McEvoy C. A randomized trial of moderately early low-dose dexametha-sone therapy in very low birth weight infants: dynamic pul-monary mechanics, oxygenation, and ventilation. Pediatrics. 2002;109(2):262–268

24. McEvoy C, Bowling S, Williamson K, McGaw P, Durand M. Randomized, double-blinded trial of low-dose dexamethasone, part II: functional residual capacity and pulmonary outcome in very low birth weight infants at risk for bronchopulmonary dysplasia.Pediatr Pulmonol.2004;38(1):55– 63

25. Ramanathan R, Siassi B, Sardesai S, deLemos RA. Comparison of two dosage regimens of dexamethasone for early treatment of chronic lung disease in very low birth weight (VLBW) infants.Pediatr Res.1994;34:250A

26. Barkemeyer BM, Davey A, Cummings JJ, et al. Pulse vs. con-tinuous dexamethasone therapy for neonatal chronic lung dis-ease (CLD) in very low birthweight (VLBW) infants.Pediatr Res. 2000;47(4):276A

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28. Bloomfield FH, Knight DB, Harding JE. Side effects of 2 differ-ent dexamethasone courses for preterm infants at risk of chronic lung disease: a randomized trial.J Pediatr.1998;133(3): 395– 400

29. Armstrong DL, Penrice J, Bloomfield FH, Knight DB, Dezoete JA, Harding JE. Follow up of a randomised trial of two different courses of dexamethasone for preterm babies at risk of chronic lung disease. Arch Dis Child Fetal Neonatal Ed. 2002;86(2): F102–F107

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birth: children reviewed with ease at 2 years differ from those followed up with difficulty.Arch Dis Child Fetal Neonatal Ed. 1998;79(2):F83–F87

31. Doyle LW, Halliday HL, Ehrenkranz RA, Davis PG, Sinclair JC. Impact of postnatal systemic corticosteroids on mortality and cerebral palsy in preterm infants: effect modification by risk for chronic lung disease.Pediatrics.2005;115(3):655– 661 32. Doyle L, Davis P, Morley C. Effect of AAP statement regarding

postnatal corticosteroids on ongoing and future randomized, controlled trials.Pediatrics.2002;110(5):1032–1033

HOW TO THINK ABOUT THE WORLD’S PROBLEMS

“The pain caused by the global food crisis had led many people to belatedly realize that we have prioritized growing crops to feed cars instead of people. That is only a small part of the real problem. This crisis demonstrates what happens when we focus doggedly on one specific—and—inefficient—solu-tion to one particular global challenge. A reducspecific—and—inefficient—solu-tion in carbon emissions has become an end in itself. The fortune spent on this exercise could achieve an astounding amount of good in areas that we hear a lot less about. Research for the Copenhagen Consensus, in which Nobel laureate economists analyze new research about the costs and benefits of different solutions to world problems, shows that just $60 million spent on providing Vitamin A capsules and therapeutic Zinc supplements for under-2-year-olds would reach 80% of the infants in Sub-Saharan Africa and South Asia, with annual economic benefits (from lower mortality and improved health) of more than $1 billion. That means doing $17 worth of good for each dollar spent. Spending $1 billion on tuberculosis would avert an astonishing one million deaths, with annual benefits adding up to $30 billion. This gives $30 back on the dollar. . . . Heart disease represents more than a quarter of the death toll in poor countries. Developed nations treat acute heart attacks with inexpensive drugs. Spending $200 million getting these cheap drugs to poor countries would avert 300 000 deaths in a year. A dollar spent on heart disease in a developing nation will achieve $25 worth of good. Contrast that to Operation Enduring Freedom, which Copenhagen Consensus research found in the two years after 2001 returned 9 cents for each dollar spent. Or with the 90 cents Copenhagen Consensus research shows is returned for every $1 spent on carbon mitigation policies.”

Lomborg B.Wall Street Journal. May 22, 2008 (Mr. Lomborg, organizer of Copenhagen Consensus, is the author of

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DOI: 10.1542/peds.2007-2258

2008;122;92

Pediatrics

Wes Onland, Anne P. De Jaegere, Martin Offringa and Anton H. van Kaam

Disease: A Meta-analysis

Neurodevelopmental Sequelae in Preterm Infants at Risk for Chronic Lung

Effects of Higher Versus Lower Dexamethasone Doses on Pulmonary and

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DOI: 10.1542/peds.2007-2258

2008;122;92

Pediatrics

Wes Onland, Anne P. De Jaegere, Martin Offringa and Anton H. van Kaam

Disease: A Meta-analysis

Neurodevelopmental Sequelae in Preterm Infants at Risk for Chronic Lung

Effects of Higher Versus Lower Dexamethasone Doses on Pulmonary and

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Figure

TABLE 1Methods of Included Studies
TABLE 4Primary and Secondary Outcomes
FIGURE 2Meta-analysis of the combined outcome of death and ce-

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