Despite significant progress in the treatment of preterm neonates, bronchopulmonary dysplasia (BPD) continues to be a major cause of neonatal morbidity. Affected infants suffered from long-term pulmonary and nonpulmonary sequel. The pulmonary sequels include reactive airway disease and asthma during childhood and adolescence. Nonpulmonary sequels include poor coordination and muscle tone, difficulty in walking, vision and hearing problems, delayed cognitive development, and poor academic achievement. As inflammation seems to be a primary mediator of injury in pathogenesis of BPD, role of steroids as antiinflammatory agent has been extensively studied and proven to be efficacious in management. However, evidence is insufficient to make a recommendation regarding other glucocorticoid doses and preparations. Numerous studies have been performed to investigate the effects of steroid. The purpose of this paper is to evaluate these studies in order to elucidate the beneficial and harmful effects of steroid on the prevention and treatment of BPD.
Despite significant progress in the treatment of preterm neonates, bronchopulmonary dysplasia (BPD) continues to be a major cause of neonatal morbidity. At earlier times, it was considered to be primarily iatrogenic in etiology as a consequence of crude ventilator techniques. In current time with advanced and sophisticated ventilator techniques, BPD continued to be a major sequel of neonatal respiratory distress syndrome (RDS), primarily because of better survival of extreme premature babies with other factors including ventilator-induced lung injury, exposure to oxygen, and inflammation. New bronchopulmonary dysplasia (new BPD) is characterized, in part, by arrested alveolar and vascular development of the immature lung [
The proposed etiology of new BPD is the initiation of inflammatory mediators that cause impairment of alveolarization and vasculogenesis [
As inflammation seems to be primary mediator of injury in pathogenesis of BPD, role of steroids as anti-inflammatory agent has been extensively studied and proven to be efficacious in management. But studies in last one and half decade have seriously questioned the routine use of steroids especially high-dose dexamethasone due to its long-term effect on neurodevelopment. In 2010, the American Academy of Pediatrics (AAP) revised policy statement regarding the use of postnatal corticosteroids for prevention or treatment of chronic lung disease in preterm infants, concluded that high-dose dexamethasone (0.5 mg/kg/day) does not seem to confer additional therapeutic benefit over lower doses, and is not recommended. Evidence is insufficient to make a recommendation regarding other glucocorticoid doses and preparations. The clinician must use clinical judgment when attempting to balance the potential adverse effects of glucocorticoid treatment with those of BPD. Postnatal use of dexamethasone for BPD has decreased since the publication of the AAP statement in 2002; however, the incidence of BPD has not decreased [
Various mechanisms have been described for beneficial effect of steroids on lung mechanics in infants with BPD. Various steroids of different potency have been studied at various timings; in different dosing regimens; for different duration; in different forms (including intravenous, inhalational, intratracheal, and recently intratracheal with surfactant as a vehicle). Amongst systemically used steroids, dexamethasone comes as the most potent and most studied one. It has been studied in early (<7 days), moderately early (7–14 days) and late/delayed (>14 days), postnatal periods and dosing ranging from 0.1 mg/kg/day to 0.5 mg/kg/day and duration ranging from 3 days to 42 days. Hydrocortisone comes second. Beclomethasone is the most commonly used inhalational steroid for BPD. Recently, budesonide has been tried as intratracheal instillation with or without surfactant as a vehicle and shown to reduce inflammatory marker in tracheal aspirates in initial clinical trials.
As the pathogenesis of BPD is multifactorial, so are the mechanisms to respond to steroid therapy. Since inflammation seems to play a critical role in the evolution of BPD, benefit seen with glucocorticoids most likely mediates through its anti-inflammatory effect.
The primary anti-inflammatory effect of glucocorticoids is mediated by annexin-1 synthesis. Annexin-1 suppresses phospholipase A2 expression, thereby blocking eicosanoids (i.e., prostaglandins, thromboxanes, prostacyclins, and leukotrienes) and the subsequent leukocyte inflammatory events including adhesion and migration. Thus, glucocorticoids inhibit two main products of inflammation prostaglandins and leukotrienes. In addition, glucocorticoids also suppress both cyclooxygenase I and II similar to NSAID, potentiating the anti-inflammatory effect [
Lung inflammation is downregulated by dexamethasone therapy. Groneck et al. evaluated the tracheobronchial aspirate from preterm infants at high risk of BPD. The number of neutrophils and concentrations of leukotriene B4, interleukin-1, elastase-
Glucocorticoids block the release of arachidonic acids and its subsequent conversion to eicosanoids. The decreased incidence of patent ductus arteriosus (PDA) after prenatal or postnatal steroid therapy is likely due to the influence of the corticosteroid effect on the responsiveness of ductal tissue to prostaglandins. Prostaglandin has an important role in maintaining the integrity of gastrointestinal mucosa. The use of steroids may increase the risk of gastrointestinal perforation. Other mechanisms such as modulating the transcription and posttranscriptional regulation of surfactant component, stimulation of antioxidant production, and enhancement of adrenergic activities may also be responsible for the acute and rapid improvement of pulmonary function [
Dexamethasone is a potent, long-acting steroid with exclusive glucocorticoid effect. When compared to hydrocortisone, dexamethasone is 25–50 times more potent. The half-life is 36–54 hours. Dexamethasone has been extensively studied in neonatal medicine and has shown to improve pulmonary function, facilitate extubation, and decrease the incidence of BPD [
On the other hand, hydrocortisone has almost equal glucocorticoid and mineralocorticoid action, and the half-life is only 8 hours. Sick premature infants have relative adrenal insufficiency during acute illness because of developmental immaturity of the hypothalamic-pituitary-adrenal axis suggesting that an early physiological replacement of cortisol may be needed [
Another steroid betamethasone, a stereoisomer of dexamethasone, differs only in the orientation of the methyl group at position 16. However, this structural difference could be responsible for marked differences in nongenomic effects. Previous antenatal steroid studies have demonstrated that both drugs have the same effects in reducing the risk of intraventricular hemorrhage, but betamethasone has been shown to be more effective than dexamethasone in reducing the risk of neonatal death and cystic periventricular leukomalacia among very premature infants [
Inhaled glucocorticoids have been used in neonates without concomitant systemic side effects. They have been successfully used for years in asthmatic patients, but their effects on mechanical ventilated preterm infants are less impressive. The delivery of inhaled glucocorticoids in preterm infants is technically difficult, and its effectiveness has been shown to be limited. Similarly, direct intratracheal instillation of glucocorticoids alone has also not been shown to be effective. A topical glucocorticoid aerosol (budesonide, fluticasone, or beclomethasone) is administered by metered dose inhaler and spacer directly to the endotracheal tube of intubated infants. In an animal model, delivery of beclomethasone to the lungs of an intubated neonate was only 1-2% of the original aerosolized drug [
A recent study from Yeh et al. suggested that intratracheal instillation of budesonide, a strong local glucocorticoids, using surfactant as vehicle may effectively deliver the medication to the lung and may decrease the incidence of BPD [
The potential mechanism of glucocorticoids in premature infants with RDS is not exactly known. Most of the clinical trials only evaluated clinical responses and did not study mechanisms explaining the beneficial effects. Based on the pathologic and physiologic studies, it seems that steroid therapy given at different times may mediate physiologic effect via different mechanisms. Premature infants may develop lung injury shortly after birth and during the first 1-2 weeks after exposure to infection, oxygen, or positive pressure ventilation. Therefore, steroid should be given shortly after birth or during the first few weeks to prevent BPD via its anti-inflammatory action. On the other hand, steroid therapy given at 3–6 weeks of life may derive its benefits from the modulation of lung repair. Alternately, steroids given at any age may be effective in infants with BPD by blunting hyperreactivity and inflammation.
Most recent studies used a dose of dexamethasone 0.1–0.5 mg/kg/day, equivalent to 10 to 20 times of endogenous corticosteroid levels, in durations ranging from 3 to 42 days. The high dosage and long duration of treatment might be responsible for the delay of brain growth and subsequent poor neurodevelopmental outcomes. A lower dose and shorter duration of dexamethasone may be beneficial and without significant side effects. However, the proper dosage and duration of treatment has not been well defined.
Compare to dexamethasone, the dosage of hydrocortisone used in the trials aimed to prevent BPD was smaller, ranging from 1-2 mg/kg/day, which is equivalent to 1 to 2 times the physiological level. Unfortunately, the low-dose replacement showed no reduction of BPD.
Current evidence suggests that dexamethasone may decrease mortality rates, facilitate extubation, and generally decrease the incidence of BPD but that it carries a significant risk for short- and long-term adverse effects, especially impairment of growth and neurodevelopment [ Cochrane database systemic review concluded that the benefits of dexamethasone therapy in the first week of life may not outweigh its many adverse effects [ Two other systemic meta-analyses have been done recently. In the first review, a risk-weighted meta-analysis, the authors emphasized the importance of the a priori risk of death or BPD in different study populations [ Small individual randomized controlled trials (RCTs) that directly compared high-versus low-dexamethasone doses, variably defined, have revealed no differences in efficacy (Table Three RCTs have compared dexamethasone to placebo (Table Many short-term adverse effects of dexamethasone therapy have been described; however, the main reason for the decline in its use is an adverse effect on neurodevelopment, particularly higher rates of CP. Eleven RCTs have been done to evaluate long term neurodevelopmental outcome (Table Cohort studies of dexamethasone have revealed an association of its use with impaired neurodevelopmental outcomes [ Authors of small series have also reported that infants treated with dexamethasone have more abnormalities on MRI than those not treated; again, causation cannot be attributed in the absence of an RCT [
RCTs of dexamethasone to prevent or treat BPD reported since 2001.
Study, no. of centers | Eligibility criteria (all on mechanical ventilation) | Timing | Dexamethasone dosing regimen | Outcome | |
---|---|---|---|---|---|
McEvoy et al. [ | 62 | 500–1500 g BW; ≤32 wk gestation | 7–21 postnatal days | 5 mg/kg/day tapered over 7 days versus 0.2 mg/kg tapered over 7 days | Rate of survival without BPD 76% versus 73% (NS); no benefit to higher dose |
Odd et al. [ | 33 | ≤1250 g BW | 1–3 wk of age | 0.5 mg/kg/day tapered over 42 days versus “individualize” (same dose, shorter course) | Rate of survival without BPD: 24% versus 30% (NS); no difference in 18-month outcomes |
Malloy et al. [ | 16 | <1501 g BW; <34 wk gestation | <28 postnatal days | 0.5 mg/kg/day tapered over 7 days versus 0.08 mg/kg/day for 7 days | Rate of survival without BPD: 11% versus 38% (NS); higher dose had more adverse effects, no apparent benefit |
Walther et al. [ | 36 | ≥600 g BW; 24–32 wk gestation | 7–14 d postnatal age | 0.2 mg/kg/day tapered over 14 days versus placebo | Rate of survival without BPD: 65% versus 47% (NS); extubation: 76% versus 42% ( |
Anttila et al. [ | 109 | 500–999 g BW; ≤31 wk gestation | Eligible at 4 h of age | 0.25 mg/kg every 12 h × 4 doses versus placebo | Rate of survival without BPD: 58% versus 52% (NS) |
Doyle et al. [ | 70 | <1000 g BW; <28 wk gestation | >1 wk postnatal age | 0.25 mg/kg every 12 h × 4 doses versus placebo | Rate of survival without BPD: 14% versus 9% (NS); extubation: 60% versus 12% (odds ratio: 11.2 (95% confidence interval: 3.2–39.0)) |
Rozycki et al. [ | 61 | 650–2000 g BW | ≥14 day postnatal age | 0.5 mg/kg/day tapered over 42 day versus inhaled beclomethasone at 3 different doses for 7 days followed by the above-listed dexamethasone course, if still mechanically ventilated | Rate of survival without BPD: 53% versus 46% (NS); extubation by 7 d: 7 of 15 versus 6 of 46 ( |
BW = body weight; NS = not significant.
Neurodevelopmental follow-up of dexamethasone RCTs reported after 2001.
Study, planned age at followup | Followup, % (no. of infants seen) | Treatment start time | Dexamethasone dosing regimen | Primary neurodevelopmental findings |
---|---|---|---|---|
McEvoy et al. [ | 66 (39) | At 7–21 days | High versus low dose: 7-day taper from 0.5 mg/kg/day versus 0.2 mg/kg/day | MDI < 70: 24% (high) versus 17% (low) (NS); |
Armstrong et al. [ | 96 (64) | On day 7 | 42-d taper versus 3-day pulse | No difference in 18-month outcomes |
Doyle et al. [ | 98 (58) | After 7 days | 0.15 mg/kg/day tapered over 10 days | Death or major disability: 46% versus 43% (NS); death or CP: 23% versus 37% (NS); CP: 14% versus 22% (NS); major disability 41% versus 31% (NS) |
Stark et al. [ | 74 (123) | On day 1 | 0.15 mg/kg/day tapered over 7 days | MDI < 70: 51% versus 43% (NS); PDI < 70: 30% versus 35% (NS); abnormal neurologic exam: 25% each group |
Romagnoli et al. [ | 100 (30) | On day 4 | 0.5 mg/kg/day tapered over 1 wk | No differences in any parameter; CP: 9% versus 14% (NS) |
Wilson et al. [ | 84 (127) | Before 3 days | 4 groups: 0.5 mg/kg/day tapered over 12 days versus late (15 days) selective, versus inhaled early or late selective | No difference in cognitive, behavioral, CP, or combined outcomes |
Yeh et al. [ | 92 (146) | On day 1 | 0.5 mg/kg/day for 1 wk, then tapered for a total of 28 days | Treated children were shorter ( |
O'Shea et al. [ | 89 (84) | On day 15–25 | 0.5 mg/kg/day tapered over 42 days versus placebo | Death or major NDI: 47% versus 41% (NS); major NDI alone: 36% versus 14% ( |
Gross et al. [ | 100 (22) | On day 14 | 0.5 mg/kg/day tapered over 42 days versus 18-day taper versus placebo | Intact survival (IQ > 70, normal neurologic exam, regular classroom): 69% versus 25% (18-d course) versus 18% (placebo) ( |
Jones and the Collaborative Dexamethasone Trial Follow-up Group [ | 95 (150) | At 2–12 wk | 0.5 mg/kg/day for 7 days | No difference in moderate/severe disability (defined as IQ > 2 SDs < mean, CP, hearing or vision loss); CP: 24% versus 15% (relative risk: 1.58 [95% confidence interval: 0.81–3.07]) |
NDI: neurodevelopmental impairment; PDI: psychomotor developmental index; NS: not significant.
In summary, high daily doses of dexamethasone have been linked frequently to adverse neurodevelopmental outcomes, and this therapy is discouraged. Because an increase in adverse neurodevelopmental outcomes in treatment studies that used low doses of dexamethasone has not been reported, further studies of low-dose dexamethasone to facilitate extubation are warranted.
Four RCTs designed to evaluate the ability of early hydrocortisone therapy to improve rates of survival without BPD have been done in recent times (Table
Neurodevelopmental outcomes at 18 to 22 months’ corrected age have been published for 3 of these trials, and no adverse effects of hydrocortisone treatment were found [
Hydrocortisone therapy given to facilitate extubation has been studied in cohort studies. In the first reported study, 25 infants treated with hydrocortisone at 1 hospital (5 mg/kg per day, tapered over 3 weeks) were compared with 25 untreated infants at the same hospital and additionally with a cohort of 23 infants treated with dexamethasone (0.5 mg/kg per day, tapered over 3 weeks) at a separate hospital [
RCTs of early hydrocortisone to prevent BPD.
Study, no. of centers | Population: mechanically ventilated infants | Timing | Hydrocortisone dosing regimen | Rate of survival without BPD HC versus placebo, % | |
---|---|---|---|---|---|
Watterberg et al. [ | 40 | BW: 500–999 g | <48 h postnatal age | 0.5 mg/kg every 12 h for 9 days | 60 versus 35 ( |
Watterberg et al. [ | 360 | BW: 500–999 g | <48 h postnatal age | 0.5 mg/kg every 12 h for 12 days | 35 versus 34 (OR: 1.20 (95% CI: 0.72–1.99)) |
Peltoniemi et al. [ | 51 | BW: 501–1250 g | <36 h postnatal age | 2.0 mg/kg/day tapered to0.75 mg/kg/day over 10 days | 64 versus 46 (OR: 1.48 (95% CI: 0.49–4.48)) |
Bonsante et al. [ | 50 | BW: 500–1249 g | <48 h postnatal age | 0.5 mg/kg every 12 h for 9 days; | 64 versus 32 ( |
As discussed before, many RCTs have shown adverse neurodevelopmental outcomes after postnatal dexamethasone treatment for BPD, but neither multicenter RCTs nor cohort studies have revealed adverse effects on functional or structural neurologic outcomes after neonatal hydrocortisone therapy. Possible reasons could be as follows. Dissimilar effective glucocorticoid dose-neonatal animal studies have consistently revealed adverse effects on brain growth after high doses of glucocorticoid [ There are dissimilar effects of these agents on the hippocampus, an area of the brain critical to learning, memory, and spatial processing [
Whatever the underlying explanation(s) for the observed differences in short- and long-term outcomes may be, further RCTs are needed to answer the many remaining questions, including whether lower doses of dexamethasone can avoid previously observed adverse effects, whether hydrocortisone is efficacious for extubation, whether specific groups of infants may derive particular benefit from hydrocortisone therapy, and whether the incidence of spontaneous gastrointestinal perforation during early glucocorticoid administration can be decreased by avoiding concomitant indomethacin or ibuprofen therapy and/or by monitoring cortisol concentrations.
No available evidence support use of other systemic glucocorticoids, such as prednisone or methylprednisolone, to treat or prevent BPD.
Although some tertiary care Neonatal ICUs routinely use inhaled beclomethasone for BPD babies, no available evidence support the efficacy of inhaled glucocorticoids to prevent or decrease the severity of BPD. Recent Cochrane database systemic review concluded “there is no evidence that inhaling steroids prevent chronic lung disease or the number of days the baby needed breathing support and additional oxygen” [
Beclomethasone and flunisolide have been studied by nebulization in view of decreasing need for systemic steroid and side effects. The early postnatal administration of inhaled steroid to prevent BPD was studied in a large randomized, multicenter trial [
Aerosolized drugs may be ineffective in preterm infants as very little drug is delivered to the lung, thereby limiting its effects. Novel idea of using surfactant as a vehicle to administer budesonide has been under study. A recent study by Halliday et al. demonstrated that intratracheal instillation of budesonide using surfactant as a vehicle significantly decreased the combined outcome of death and CLD without apparent immediate and long-term adverse effects [
High daily doses of dexamethasone (approximately 0.5 mg/kg per day) have been shown to reduce the incidence of BPD but have been associated with numerous short- and long-term adverse outcomes, including neurodevelopmental impairment, and at present, there is no basis for postulating that high daily doses confer additional therapeutic benefit over lower-dose therapy.
Low-dose dexamethasone therapy (<0.2 mg/kg per day) may facilitate extubation and may decrease the incidence of short- and long-term adverse effects observed with higher doses of dexamethasone. Additional RCTs sufficiently powered to evaluate the effects of low-dose dexamethasone therapy on rates of survival without BPD, as well as on other short- and long-term outcomes, are warranted.
Low-dose hydrocortisone therapy (1 mg/kg per day) given for the first 2 weeks of life may increase rates of survival without BPD, particularly for infants delivered in a setting of prenatal inflammation, without adversely affecting neurodevelopmental outcomes. Clinicians should be aware of a possible increased risk of isolated intestinal perforation associated with early concomitant treatment with inhibitors of prostaglandin synthesis. Further RCTs powered to detect effects on neurodevelopmental outcomes, aimed at targeting patients who may derive most benefit and developing treatment strategies to reduce the incidence of isolated intestinal perforation, are warranted.
Higher doses of hydrocortisone (3–6 mg/kg per day) instituted after the first week of postnatal age have not been shown to improve rates of survival without BPD in any RCT. RCTs powered to assess the effect of this therapy on short- and long-term outcomes are needed.
BPD is the disease of very low birth weight and extremely low birth weight newborns with multifactorial etiology including prematurity itself, ventilator-induced injury, oxygen, and inflammation. BPD has long-term adverse pulmonary and neurodevelopment outcome. Steroids usage for treatment of BPD also has been shown to have adverse neurodevelopmental outcome. Available data are conflicting and inconclusive; clinicians must use their own clinical judgment to balance the adverse effects of BPD with the potential adverse effects of treatments for each individual patient. Very low birth weight infants who remain on mechanical ventilation after 1 to 2 weeks of age are at very high risk of developing BPD [
This work was supported in part by the National Health Research Institute, Taiwan (NHRI-EX99-9818PI).