The prevention and management strategies for neonatal chronic lung disease

ABSTRACT

Introduction

Survival from even very premature birth is improving, but long-term respiratory morbidity following neonatal chronic lung disease (bronchopulmonary dysplasia (BPD)) has not reduced. Affected infants may require supplementary oxygen at home, because they have more hospital admissions particularly due to viral infections and frequent, troublesome respiratory symptoms requiring treatment. Furthermore, adolescents and adults who had BPD have poorer lung function and exercise capacity.

Areas covered

Antenatal and postnatal preventative strategies and management of infants with BPD. A literature review was undertaken using PubMed and Web of Science.

Expert opinion

There are effective preventative strategies which include caffeine, postnatal corticosteroids, vitamin A, and volume guarantee ventilation. Side-effects, however, have appropriately caused clinicians to reduce use of systemically administered corticosteroids to infants only at risk of severe BPD. Promising preventative strategies which need further research are surfactant with budesonide, less invasive surfactant administration (LISA), neurally adjusted ventilatory assist (NAVA) and stem cells. The management of infants with established BPD is under-researched and should include identifying the optimum form of respiratory support on the neonatal unit and at home and which infants will most benefit in the long term from pulmonary vasodilators, diuretics, and bronchodilators.

KEYWORDS:

• Bronchopulmonary dysplasia
• surfactant
• corticosteroids
• caffeine
• macrolides
• stem cells
• diuretics
• respiratory support

1. Introduction

Survival from even very premature birth is improving in many countries, but long-term respiratory morbidity following neonatal chronic lung disease or bronchopulmonary dysplasia (BPD) has not reduced [1]. BPD was originally described in infants with severe respiratory disease who required high peak pressures and levels of supplemental oxygen during mechanical ventilation resulting in fibrosis and emphysematous alveolar areas. Routine use of antenatal steroids and postnatal surfactant decreased the incidence of respiratory distress syndrome (RDS) and mortality [2,3], but not BPD. The subsequent description of ‘new’ BPD highlighted that prematurely infants who did not receive artificial ventilation could require supplementary oxygen at 36 weeks post-menstrual age (PMA) [4]. There have been many definitions of BPD, a consensus statement in 2001 defined BPD as oxygen dependence at 28 days and then the severity was determined at 36 weeks PMA as mild, moderate, or severe depending on the level of respiratory support then required [4]. The cardinal feature of new BPD is arrested development with simplification of the lungs – impairment of both alveolarization and vascularization of the pulmonary vessels. These changes are in part driven by a systemic inflammatory cascade. BPD is most commonly seen in infants born prematurely but can also occur in infants with conditions associated with pulmonary hypoplasia, such as congenital diaphragmatic or anterior wall defect. Poor intrauterine growth is associated with an increased risk of BPD [5] and worse lung function at follow-up [6,7]. There, however, have been conflicting results from studies investigating whether chorioamnionitis increases the risk of BPD. In some, the risk disappeared once the earlier gestational age at birth of the chorioamnionitis exposed infants was taken into account. A large meta-analysis [8] demonstrated a significant relationship between chorioamnionitis and BPD, and there is some evidence that wheezing may be increased at follow-up of infants exposed to chorioamnionitis [9]. Males have a higher incidence of BPD, which relates to their more immature lung structure at birth, and they have poorer lung function in childhood and adulthood [10,11].

A worldwide review showed that BPD was a global problem, but the incidence reported by different countries varied between 10% and 89% [12]. In Europe and North America, the incidence has been reported to be as high as 80% in those born at the lowest gestations.

BPD occurs more commonly in those infants born prematurely (less than 37 weeks of gestational age) or very low birthweight (VLBW less than 2500 gms) than those born at term. It particularly occurs in those born extremely premature (less than 29 weeks of gestational age) or extremely low birthweight (ELBW less than 1000gms).

The chronic lung disease related to prematurity has been shown to have consequences beyond discharge from the neonatal unit. Infants may require supplementary oxygen at home, because they have more hospital admissions than those without BPD particularly due to viral infections and have frequent, troublesome respiratory symptoms requiring treatment. Furthermore, studies of lung function in adolescents [10] and adults [13] have shown that those who had BPD had poorer lung function compared to those who did not. Adults born prematurely who developed BPD had poorer airway function compared to those without BPD and those born at term [11]. At 35 years, those born extremely preterm or extremely low birthweight had six times the risk for chronic obstructive pulmonary disease [14,15]. In addition, they have poorer exercise capacity [16]; 39 young people born before 29 weeks of gestation had an abnormal forced expiratory flow at 75% (FEF75) (<5^th percentile) with a reduced sprint distance of 114 m and 27 having a very abnormal FEF75 (<2.5 percentile) had a reduced sprint distance of 159 m. Putting those results in context, adults in a cardiac rehabilitation program undertaking regular modified shuttle sprint tests had a modified shuttle sprint test difference of 70 m [17], thus a difference of 159 m is clinically significant [17]. Puberty is the last positive effector of lung function with rapid growth of the airways and lung parenchyma [18], yet, studies have demonstrated that lung function may deteriorate during puberty in those who had BPD [19,20], particularly if they had received postnatal corticosteroids [21]. It is important to reduce this respiratory burden. Furthermore, BPD has been associated with adverse neurodevelopmental outcomes. In a case series of 250 infants from a single center, those who had developed grade two or three BPD had worse neurodevelopmental outcomes in a grade-dependent manner. In another single center, retrospective study increased BPD severity was associated with an increased risk of neurodevelopmental delay at both 2 and 5 years [22,23]. The aim of this review, therefore, is to discuss possible preventative and management BPD strategies.

2. Methods

A literature review was undertaken using PubMed and the Web of Science with the search terms in the subheadings of the review, adding ‘neonatal,’ ‘infant,’ ‘premature,’ or ‘bronchopulmonary dysplasia’ as appropriate. Article abstracts were then screened to identify relevant articles and those with relevant findings pertinent to the expert review included ‘chronic lung disease’ or ‘bronchopulmonary dysplasia’ as appropriate. Article abstracts were then screened to identify relevant articles and those with relevant findings pertinent to the expert review included. Further articles were added to the review if cited in articles identified from the literature search. Seminal articles were included where appropriate. Meta-analyses and Cochrane reviews were preferred in the context of this review; however, individual studies were examined where data were of relevance or conflicting. Recent studies involving infants exposed to modern neonatal interventions such as antenatal corticosteroids and postnatal surfactant were used in preference. The literature search was performed independently by both authors and the results then shared in the context of writing this review.

3. Antenatal preventative strategies

3.1. Antenatal corticosteroids and thyroid stimulating hormone

Antenatal corticosteroids administered to mothers at risk of preterm delivery reduce infant mortality. A Cochrane review, however, demonstrated no significant difference in the risk of BPD (risk ratio (RR), 0.86; 95% confidence interval, 0.61–1.22) [24]. This may reflect that antenatal corticosteroids, as intra-amniotic endotoxin, impairs secondary septation [25]. Thyroid releasing hormone showed promising results in lambs, resulting in increased surfactant production and lung compliance. In human studies, no such benefit was seen and there was a suggestion of delayed motor development [26].

3.2. Sildenafil

Sildenafil has been trialed as an intervention to improve fetal growth and reduce the associated neonatal morbidity. In a meta-analysis of eight small, randomized controlled trials (RCTs), enrolling 576 infants in total, doses between 3 and 20 g per day of sildenafil citrate were given to mothers in whom poor intrauterine fetal growth was identified. Growth was improved (Standardized Mean Difference 0.41, 95% CI 0.24 to 0.58) and the gestation of pregnancy lengthened (SMD 0.30, 95% CI 0.07, 0.51) [27]. There were, however, no significant differences in the infant clinical outcomes investigated (mortality and respiratory distress syndrome); rates of BPD were not reported. An interim analysis of a large randomized trial of Sildenafil (the STRIDER trial [28]) led to the halting of the trial after 11 infants died in the treatment arm compared to none in the placebo arm [29].

4. Postnatal preventative strategies

4.1. Surfactant therapy

Surfactant production is detected in the fetal lung from the 22 weeks of gestation, but only reaches maturity at 33 to 34 weeks [30]. Surfactant deficiency can result in severe RDS and death in prematurely born infants [31]. Surfactant administration to treat RDS reduces mortality, but not BPD [2]. A comparison of prophylactic and selective surfactant administration [32] demonstrated a non-significant trend in reducing the requirement for oxygen at 28 days in favor of selective use, but there was no significant difference in the requirement for oxygen at 36 weeks corrected weeks gestational age. In the TOLSURF randomized trial of infants less than 29 days of gestational age who continued to require mechanical ventilation between 7 and 14 days after birth, infants received inhaled nitric oxide with either surfactant or a placebo every 1 to 3 days up to a maximum of five doses. There was no significant effect of late surfactant use on survival without BPD development [33], but at 1 year of age infants who received late surfactant required fewer post-discharge hospital admissions for respiratory problems [34].

The mode of surfactant delivery has also been examined [35,36]. In a meta-analysis of six trials recruiting in total 895 infants born between 23 and 34 weeks of gestation, who were randomized to either intubation (including INSURE only and those ventilated beyond the delivery room) versus less invasive surfactant administration (LISA), showed that LISA undertaken once infants were admitted to the neonatal unit was associated with a reduced risk ratio of the combined outcome of BPD or death [37]. In a subsequent study of 485 infants with a gestational age of 25 to 28 weeks with RDS, minimally invasive surfactant administration when the infants required 30% or more of supplemental oxygen was not associated with a significant reduction in death or BPD. In another study, infants given LISA in the delivery suit had a lower respiratory rate and oxygen requirement following surfactant administration compared to historical controls, suggesting that LISA reduced respiratory distress [38]. LISA in delivery suite was also demonstrated to reduce days of ventilation and BPD compared to routine care [39]. No trials, however, have compared delivery suite LISA to later administration. In addition, there remains significant variation in LISA techniques, premedication use, and subsequent respiratory management [40].

4.2. Respiratory support

Invasive mechanical respiratory support can be lifesaving but can increase the risk of BPD, particularly if high pressures and/or high-inspired oxygen levels are used. Studies, therefore, have focused on providing alternative treatments to invasive mechanical support or by limiting the damage done by such support.

4.2.1. Noninvasive mechanical ventilation

Continuous positive airway pressure as an alternative to intubation and ventilation was not shown to reduce the incidence of BPD in one systematic review [41]. A more recent review, however, demonstrated that although there was insufficient evidence to evaluate prophylactic continuous positive airway pressure (CPAP) compared to oxygen therapy, when compared to mechanical ventilation, it reduced BPD and the combined outcome of death and BPD [42]. Synchronized noninvasive positive pressure ventilation (sNIPPV) reduced the need for reintubation following extubation from mechanical ventilation compared to CPAP alone [43], as well as reducing BPD, although this outcome was reported in only three small trials.

Heated humidified high flow nasal cannula (HHHFNC) oxygen has increased in popularity within neonatal units over recent years. A systematic review of 13 studies, however, showed no benefit in the prevention of BPD when using HHHFNC compared to CPAP when used as the primary mode of respiratory support or after extubation [44]. HHHFNC can facilitate earlier feeding with faster weight gain and weaning from supplementary oxygen in those infants requiring support beyond 32 weeks [45].

4.2.2. Volume targeted ventilation (VTV)

In vitro and pre-clinical studies showed that high tidal volumes during mechanical ventilation led to release of inflammatory interleukins and subsequent damage to the lung parenchyma. Tidal volumes of 4 to 7 ml/kg are normally targeted during VTV, whereas without volume targeting, volumes of up to 10 ml/kg can be delivered [46]. In a Cochrane review, VTV compared to pressure-limited, time-cycled ventilation reduced the incidence of BPD within the prematurely born population [47]. In infants with a birthweight less than one kilo, however, there was no significant difference in the rate of BPD. The range of tidal volumes used in the studies varied significantly and lower tidal volumes can be pro-inflammatory as can higher tidal volumes [48]. Furthermore, during acute respiratory distress, higher rather than lower volumes within the tidal volume range were associated with a lower work of breathing [49,50]. Among infants with evolving or established BPD, a target tidal volume of 7mls/kg was associated with a reduced work of breathing significantly below baseline [51], likely reflecting the increased physiological dead space of infants with BPD.

4.2.3. High frequency oscillation ventilation

High-frequency oscillation ventilation (HFOV) results in smaller tidal volumes being delivered to an infant than during conventional ventilation [52]. In vitro studies have shown that the inflammatory interleukin release from cells undergoing oscillation-like stretch was lower than cells stretched in a way that mimicked conventional ventilation [53]. A Cochrane review highlighted that prophylactic HFOV was associated with a significant, but borderline reduction in moderate-to-severe BPD [54], but the study designs differed, as did the oscillators and most importantly the control respiratory support used. A subsequent individual patient meta-analysis found no significant difference in the rates of BPD between those receiving HFOV or conventional mechanical ventilation (CMV) [55]. The UKOS trial randomized 797 infants born at less than 29 weeks of gestation to receive either conventional or oscillatory ventilation within an hour of birth [56]. The study found no significant difference in the primary combined outcome of BPD or death, however, subsequent follow-up at 11 to 14 years of age showed better airway function in those who received HFOV [57]. When examined again at 16 to 19 years of age, the differences were smaller and no longer statistically significant suggesting that pubertal growth may have caused the conventionally supported group’s lung function to catch up [58].

The use of volume-targeted high-frequency oscillation (HFOV-VG) has been suggested to reduce the inflammatory effect of mechanical ventilation. There are, however, no randomized studies comparing HFOV-VG with conventional ventilation, but one retrospective study highlighted a reduction in BPD [59].

4.2.4. Neurally adjusted ventilator assist

In neurally adjusted ventilator assist (NAVA), the ventilator trigger and ‘assistance’ are governed by the electrical activity of the diaphragm measured by electrodes on a modified nasogastric tube. Crossover studies of infants with evolving or established BPD have demonstrated that NAVA, when compared to conventional ventilation, resulted in a lower mean airway pressure requirement, a better oxygen index, and a better oxygenation as measured by the alveolar-arterial gradient [60,61]. A Cochrane review comparing NAVA to other triggered modes of ventilation found only one eligible randomized trial [62]. In that study of 60 infants, whilst ventilator parameters improved on NAVA used as rescue support compared to the control group, there was no significant difference seen in the rate of BPD [63]. A single center study comparing the outcomes of infants who received noninvasive or invasive NAVA with that of historical controls reported no significant difference in the incidence of BPD, but there was a reduction in the overall length of stay on the neonatal unit (112 days versus 140 days, p = 0.019) [61].

4.3. Supplementary oxygen

Hyperoxia has been shown to induce abnormal vascular growth lung tissue in vitro and in animal studies [64]. Abnormal vascular growth has been shown to be a key component of the pathophysiology of new BPD [65]. It has been suggested that this abnormal vascularization mirrors changes seen in retinopathy of prematurity [66], which is reduced by reducing the exposure of preterm infants to supplemental oxygen [67]. It is, therefore, reasonable to suspect that reducing the exposure of infants born prematurely to supplemental oxygen might reduce the incidence of BPD; however, this has not been shown in randomized trials. In a meta-analysis examining exposure to high versus low levels of supplementary oxygen during resuscitation, there was no significant difference in rates of BPD [68]. Furthermore, in a multicenter study randomizing infants born at less than 28 weeks gestation to higher or lower oxygen saturation targets on the neonatal unit, there were no significant differences seen in rates of BPD; however, more infants died in the group with lower oxygen saturation targets [69]. Thus, despite the benefits seen in vitro and in animal studies, reducing the exposure of preterm infants to supplemental oxygen requires a cautious approach given the risk of increased mortality.

4.4. Inhaled nitric oxide

A Cochrane review of inhaled nitric oxide use in preterm infants with respiratory failure examined three different timings of the intervention: early treatment (within 3 days) for impaired oxygenation (eight trials), routine use in infants requiring respiratory support (four trials), and later use in those at an increased risk of BPD (three trials) [70]. No benefits to receiving iNO were seen regarding any of the timings of iNO administration. There were, however, trends toward positive outcomes, and it could be argued that more select entry criteria to better define a high-risk population might result in more positive results. A trial of 800 infants born between 24 and 28 + 6 weeks of gestational age included those with mild disease, that is requiring surfactant or CPAP for RDS within the first 24 hours of birth. They were randomized to inhaled nitric oxide (iNO) or placebo at 5 ppm for a minimum of 7 days and a maximum of 21 days. No significant differences were found in BPD development or death [71]. At 7-year follow-up, rates of rehospitalisation and use of respiratory medications were similar between the two groups [72].

4.5. Postnatal sildenafil

The use of sildenafil to prevent BPD has been poorly studied. The effects of sildenafil in a rat model were encouraging with increased alveolarisation, improved pulmonary vascularization, reduced inflammation, and reduced right ventricular hypertrophy [73]. Whilst there is some evidence for the use of sildenafil in term infants with pulmonary hypertension where inhaled nitric oxide therapy is unavailable [74], a systematic review of its use in pulmonary hypertension associated with BPD failed to show any benefit beyond a short-term reduction in oxygen requirement [75]. In 40 infants born between 24.0 and 29.7 weeks of gestation randomized to receive oral sildenafil (0.5 mg/kg every 6 hours or a placebo), no significant differences were seen between the two groups in mortality, respiratory support at 36 weeks or side-effects [76]. Concerns had been raised regarding the use of sildenafil in children after a trial recruiting children aged between 1 and 17 years with pulmonary hypertension demonstrated an increased mortality in those who received high-dose sildenafil [77]. A randomized control trial is currently underway to investigate the safety of sildenafil in the neonatal population at different doses [78]. The trial will investigate respiratory outcomes as a secondary outcome measure.

4.6. Fluid restriction

Fluid restriction has been suggested to result in a reduction in the incidence of BPD in that when reduced volumes of fluid were given to ventilated infants as part of a package of respiratory care, the incidence of BPD was lower [79]. In a RCT including infants at high risk of developing BPD, routinely exposed to antenatal corticosteroids and postnatal surfactant, fluid restriction was not associated with a reduction in BPD, but fewer of the fluid restricted group required treatment with postnatal corticosteroids. Colloid infusion, however, was associated with an increased duration of oxygen dependency [80]. A Cochrane review highlighted the lack of studies investigating the effects of fluid restriction on the development of BPD [81].

4.7. Patent ductus arteriosus closure

A patent ductus arteriosus (PDA) for more than 10 days has been shown to increase the risk of BPD [82]. Whilst administering ibuprofen has been shown to successfully close PDAs, a Cochrane review did not find any evidence that it reduced the incidence of BPD when given prophylactically [83]. A multicentre, randomized trial attempted to recruit only those infants whose ducts were judged as haemodynamically significant enrolled 337 infants to receive either ibuprofen or no treatment [84]. The trial did not demonstrate any improvement in respiratory status with regard to ventilator days or the durations of noninvasive respiratory support or supplementary oxygen. There remains controversy regarding PDA management and its role in the pathogenesis of respiratory disease [85]. In a recently published multicentre RCT which included 273 infants, expectant management for PDA in infants born at less than 28 weeks of gestation was non-inferior to early ibuprofen treatment with respect to BPD [86].

4.8. Caffeine

Caffeine acts by increasing central respiratory drive stimulating diaphragmatic contractility has a diuretic action [87] and has anti-inflammatory properties [88,89]. In the Caffeine for Apnea of Prematurity (CAP) trial, infants were randomized if methylxanthines were thought to be required for prevention or treatment of apnea and/or facilitation of removal of an endotracheal tube in the first 10 days after birth. The primary outcome of death or neurodevelopmental disability (NDI) determined at 18 to 21 months was significantly lower in the caffeine group who also had a lower BPD rate [90]. Caffeine use was associated with a lower PDA incidence [91], which may in part have been responsible for the reduction in BPD. Early initiation of caffeine therapy was associated with a greater reduction in ventilation duration [92].

4.9. Vitamin A

Vitamin A is a group of fat-soluble compounds which maintain the integrity of epithelial cells of the respiratory tract. Premature infants are vitamin A deficient [93], and lower vitamin A levels have been documented in those who subsequently developed BPD [94]. A Cochrane review of vitamin A supplementation in very low birth weight infants or those born before 32 weeks of gestational age demonstrated Vitamin A administration was associated with a small, but significant reduction in BPD. This, however, requires repeated intramuscular injections [95]. Furthermore, a systematic review of 17 studies suggested that the benefit of vitamin A supplementation is likely to be limited to infants with baseline vitamin A intake less than 1500 IU per kg per day [96].

5. Macrolides

The inflammatory cascade has been shown to have an important role in the development of BPD with higher levels of inflammatory cytokines such as IL-6 and TNF-α in those who went on to develop severe BPD or die [97]. Colonization of the respiratory tract with Ureaplasma urealyticum has been associated with an increased incidence of BPD [98]. Ureaplasma urealyticum has been shown to induce inflammatory cytokine production including IL-6 and TNF-α both systemically and within the lungs [99,100]. It has also been shown to promote apoptosis of lung epithelial cells [101]. Azithromycin inhibits neutrophil migration, chemotaxis [102] and the subsequent release of inflammatory interleukins such as IL-6 and TNF-α [103]. It is effective in reducing the bacterial load of Ureaplasma urealyticum in preterm infants [104]. A meta-analysis of three RCTs involving 319 premature infants randomized to either azithromycin or placebo showed that prophylactic azithromycin resulted in a borderline reduction of BPD. A further meta-analysis of 529 patients randomized to azithromycin or placebo failed to demonstrate a reduction in BPD but did demonstrate a significant reduction in the length of supplemental oxygen requirement [105]. The meta-analysis, however, was very heterogenous, including trials utilizing short or long courses of azithromycin (less than or more than 7 days), and infants who did not require ventilation. Only one study reported longer-term respiratory outcomes and found no significant differences in respiratory or neurodevelopmental outcomes at 2 years of age [106]. In a trial of 220 infants, a subgroup analysis of the effect of azithromycin in those colonized with Ureaplasma urealyticum (76 patients) [107] demonstrated that there was a reduction in BPD but not a difference in Ureaplasma urealyticum colonization between the two groups. A larger multicentre, randomized trial of azithromycin versus placebo (AZTEC trial) has completed recruitment, and the results are awaited [108]. A single center trial of another macrolide, clarithromycin, in infants colonized by Ureaplasma urealyticum on day 3 after birth, showed a benefit in reducing BPD (2.9% versus 36.4%) [109].

5.1. Antioxidants

One of the multifactorial causes implicated in BPD development has been oxygen toxicity, not least as prematurely born infants have low antioxidant defenses. The enzyme superoxide dismutase (SOD) dismutates the toxic superoxide radical into the less toxic hydrogen peroxide. Nevertheless, a Cochrane review highlighted that, in two RCTs, SOD did not significantly reduce death or oxygen dependency at 28 days or 36 weeks, but, in one, there was a lower frequency of respiratory problems after discharge [110]. A systematic review of 26 trials demonstrated that vitamin E supplementation reduced the risk of intracranial hemorrhage but increased the risk of sepsis so is not recommended [111]. Further RCTs are required to identify if antioxidant supplementation will reduce BPD and more importantly improve long-term respiratory outcomes in prematurely born infants.

5.2. Postnatal corticosteroids

5.2.1. Dexamethasone

Corticosteroids are frequently administered to ventilator-dependent infants with the hope of improving respiratory function and facilitating extubation. Whilst given early (before 7 days after birth) corticosteroids reduced the incidence of BPD or death, there was an increased risk of hyperglycemia, hypertension, gastrointestinal bleeding, gastrointestinal perforation and growth failure [112]. Late administration of postnatal corticosteroids was also associated with a reduction of BPD or death [113] and whilst the incidence of hyperglycemia was increased, there were no significant differences in gastrointestinal complications or growth. It should be noted that a number of those in the placebo arms of the included studies subsequently received corticosteroids. The duration of the courses included in the meta-analysis varied, but one study demonstrated that oxygen diffusion continued to improve throughout a 9-day course; however, immature infants were less responsive to postnatal corticosteroids [114]. In an RCT which included infants of less than 28 weeks of gestational age, a 42-day tapering course compared to a 9-day course with rapid tapering was associated with decreased hospital morbidities and increased rate of survival without handicap. Only 59 infants, however, were included in the study and given the known side-effects of corticosteroids, it would be important to further explore the effects of a prolonged duration of corticosteroids before this regime is introduced into routine clinical practice [115]. Ventilated infants who go onto develop BPD frequently receive multiple courses, but there is a paucity of data on the efficacy of a second course of systemic postnatally administered corticosteroids. In a retrospective study, a second course was associated with improvements in oxygenation and successful weaning from mechanical ventilation [116]. Acutely, growth impairment can occur as a side-effect of systemically administered corticosteroids. In a whole population study of 6,104 preterm infants with BPD, of whom 28.3% received corticosteroids no significant differences were seen in weight gain or head circumference growth from birth to discharge in those that did or did not receive corticosteroids [117]. Lung function, however, was worse at 11 to 14 years and 16 to 19 years in those that received corticosteroids while on the NICU. The mean lung function was lower as the number of courses of dexamethasone increased [118]. In the unexposed group, lung function improved between 11 to 14 and 16 to 19 years but forced expiratory flow at 75% of the expired vital capacity and forced expiratory volume in 1 second deteriorated in those who received postnatal corticosteroids likely increasing their risk of the premature onset of chronic obstructive pulmonary disease [118]. Secondary analysis of the Preterm Erythropoietin Neuroprotective (PENUT) RCT demonstrated that long duration and higher cumulative dose of dexamethasone were associated with worse neurodevelopmental scores at a corrected age of 2 years [119].

5.2.2. Hydrocortisone

Hydrocortisone has been investigated as an alternative to dexamethasone due to the improved neurological side effect profile associated with hydrocortisone in laboratory studies [120]. Studies of hydrocortisone in prematurely born infants, however, have yielded conflicting results [121]. A study of hydrocortisone within French neonatal units suggested a significant benefit in survival without BPD among the 256 infants randomized to low-dose prophylactic hydrocortisone compared to the 257 who were not [122]. A subsequent trial of 800 infants in the US, who were randomized to low-dose hydrocortisone on day 14 or placebo, showed no benefit associated with receiving low-dose hydrocortisone and a higher incidence of hypertension [123]. A meta-analysis of studies utilizing hydrocortisone highlighted an increased risk of late onset sepsis and gastrointestinal perforation [124].

5.2.3. Inhaled corticosteroids

Locally acting corticosteroids delivered by inhalation or nebulization have been suggested to reduce the incidence of BPD. A study of 863 infants randomized to either budesonide or placebo, however, showed that whilst BPD was reduced in those treated with budesonide, there was a non-significant increase in mortality [125]. Follow-up of the cohort demonstrated that the increase in mortality among those who received budesonide had become statistically significant [126].

Budesonide given with surfactant at delivery has also been studied. The rationale for combining budesonide with surfactant is related to the increase in inflammatory interleukins in those who go on to develop BPD [97] and the increased solubility of budesonide when combined with surfactant [127]. In a randomized, multicentre study in which 265 infants born at less than 29 weeks gestation were randomized to either surfactant combined with budesonide or surfactant alone, the incidence of death or BPD was reduced in those who received the combination therapy [128]. In the trial, tracheal aspirates were sent from a subset of 40 infants and lower levels of inflammatory interleukins (IL-1, IL-6 and IL-8) were observed in the intervention arm [128]. At 2 years of age, however, there were no significant differences in the number of infants with respiratory symptoms or requiring respiratory medications [128]. In a study in which the outcomes of infants who received budesonide and surfactant were compared to historical controls, there were no significant differences in neurodevelopmental outcomes at 4 to 6 months or 18 to 22 months corrected age [129].

5.3. Stem cells

The lungs’ endogenous stem and progenitor cells which regenerate normal alveolarization and pulmonary vascular development are dysfunctional in BPD [130]. Mesenchymal stem cells (MSCs) are thought to possess potent immunomodulatory and secretory properties acting in a paracrine manner to modulate endogenous responses to injury and repair [131]. In a phase 1 clinical trial, the safety and feasibility of MSC transplantation was reported [132]. In a subsequent randomized controlled phase 11 trial, infants born between 23 and 28 weeks of gestation deteriorating on mechanical ventilation at 5 to 14 days were randomly allocated to receive stem cells or placebo. The primary outcome of death or BPD was not significantly improved with MSC transplantation, but in a secondary analysis, the incidence of severe BPD in the infants born at 23 to 24 weeks gestation was significantly lower, 19% compared to 53% [133].

6. Management

6.1. Diuretics

Diuretics have been studied in those developing or with established BPD. Two Cochrane reviews highlighted that whilst a transient improvement in respiratory status was seen up to a week after starting diuretics, there was no evidence that diuretics improved respiratory outcomes beyond this time [134,135]. A retrospective review over a five-year period in a single center in the era of routine antenatal corticosteroids and postnatal surfactant showed that diuretic use was associated with electrolyte abnormalities and reduction in weight gain with only slight improvement in short term respiratory status [136]. A systematic review included eight randomized studies of preterm infants less than 3 weeks of age with evolving or established BPD randomly allocated to receive an aerosolized loop diuretic or not. A single dose transiently improved respiratory mechanics, but there was no information available on the effects of chronic administration effects [137].

6.2. Inhaled bronchodilators

In a retrospective review of 1429 infants born at less than 29 weeks of gestational age, 33% had received bronchodilators. The frequency and duration of the courses were variable between centers [138], likely reflecting the lack of evidence of positive long-term benefit. Studies in ventilated infants have shown only short-term benefits, yet prolonged ventilation (>54 days) best predicted bronchodilator use [138].

6.3. Leukotriene receptor blockade

Montelukast is a selective leukotriene receptor antagonist of cysteinyl leukotriene, which causes bronchoconstriction, mucus secretion, airway hyperactivity, and increased vascular permeability [139]. In a non-randomized study, montelukast given daily for at least 3 weeks in 11 infants was associated with improved survival compared to controls and the pulmonary severity score and the duration of ventilation were lower [140]. A subsequent prospective, multicentre, RCT of 66 infants born at less than 32 weeks of gestational age with a postnatal age greater than 14 days, all ventilator or supplementary oxygen dependent demonstrated no significant difference in the incidence of moderate-to-severe BPD (43.4% versus 52.8%, p = 0.912) [141].

6.4. Anti-hypertensives

The incidence of systemic hypertension has been reported to be between 7% and 43% [142]. Infants have increased aorta wall thickness and stiffness [143], hypertrophy of the heart and reduced cardiac function [144]. Captopril, an angiotensin-converting enzyme inhibitor, may improve endothelial function and nitric oxide release [142]. In a case series of six infants with severe BPD unresponsive to sildenafil and diuretics, 5 weeks after commencing treatment with captopril, there was a significant reduction in the mean fraction of inspired oxygen and ventilatory requirements with a reduction in aorta intima media thickness [142]. Clearly, further studies are required to determine the optimum management of hypertension in this population.

6.5. Pulmonary hypertension

The incidence of pulmonary hypertension (PH) in infants with BPD ranges from 17% to 37%. In a single center study, the development of PH was associated with a lower gestational age and ventilatory support 28 days after birth. Mortality was increased in that group, as was length and healthcare cost of stay, after adjusting for gestational age [145]. The treatment of PH is based on consensus opinion, and few randomized trials have been undertaken [146]. It has been suggested that the mainstay of treatment of PH in BPD is pulmonary vascular dilatation, prevention of further lung damage, offloading the right ventricle, prevention of coronary ischemia, and improved quality of life [147]. Whilst some treatments such as sildenafil have been shown to reduce the degree of pulmonary hypertension [148], there is little evidence that this has improved overall outcomes or reduced the incidence of BPD. Indeed, one study of sildenafil showed that in the 21 infants with pulmonary hypertension, although the degree of pulmonary hypertension improved when infants received sildenafil, there was no improvement in pulmonary gas exchange or respiratory severity score [149].

A historical cohort study of 20 infants evaluated to a median age of 2 years gave an overall survival rate of 95% in those treated with either sildenafil or Bosentan [150]. Whilst the authors identified this was a lower mortality rate than other reported observational studies, they acknowledged that there were significant differences in their population, in particular the degree of severity of pulmonary hypertension.

These data would suggest that pulmonary hypertension occurs as a result of the lung damage associated with BPD but altering the degree of hypertension does not reverse or treat the underlying chronic lung disease. There is insufficient evidence to state that longer term outcomes are improved.

6.6. Nutrition

Infants with significant respiratory morbidity have an increased basal metabolic rate requiring increased calorie intake to preserve normal growth velocities [151]. Furthermore, it has been shown that delayed introduction of proteins and nutrition in a preterm population is associated with poor growth [152]. In one trial investigating the effect of early standardized, concentrated, macronutrients, parenteral nutrition in infants born less than 29 weeks, there was no significant difference reported in the rates of BPD at 36 weeks between the 74 infants in the intervention arm and the 76 infants in the standard care arm [153]. The intervention group, however, had better growth at 36 weeks PMA (mean difference 0.40, 95% CI 0.005 to 0.79). The role of nutrition in the development of BPD is multifactorial [154], but those data suggest that simply improving growth may not improve respiratory outcomes.

6.7. Home respiratory support

The majority of infants are usually able to be weaned off home oxygen before 12 months of age [154–158]. Exposure to secondhand smoke, however, has been associated with a trend for longer duration of supplemental home oxygen [154]. Infants with severe BPD when ventilated at home have to be able to trigger a portable ventilator [159]. Portable ventilators may have less rapid response times. It is, therefore, important to transition infants early on to portable home ventilators so that the most appropriate ventilator can be identified. Studies are required to develop devices to optimize home ventilation.

6.8. Immunization

Respiratory syncytial virus (RSV) is an important cause of readmission, morbidity, and mortality among preterm infants [160]. A monoclonal antibody, palivizumab, has been shown to reduce hospital admissions and admissions to intensive care [161]. The cost of immunization is substantial, and therefore cost analyses have been performed to mitigate the costs by targeting those most at risk of the severe consequences of RSV infection, for example, infants requiring home oxygen at discharge [162].

7. Expert opinion

Bronchopulmonary dysplasia (BPD) is the most common long-term adverse outcome of very premature delivery and is associated with chronic respiratory morbidity. It should be noted, however, that extremely prematurely born infants who did not develop BPD may also suffer such a long-term adverse respiratory outcome. As a consequence, it is important to assess the long-term efficacy of all treatment strategies in extremely preterm infants regardless of the development of BPD. Prediction of infants at high risk of chronic respiratory morbidity could facilitate targeting of interventions within and out with randomized controlled trials. Cluster analysis may provide a method of identifying discrete groups of prematurely born infants with differing respiratory outcomes during the first 7 years. In a study of 168 infants, readily available clinical data were used to classify them into hierarchical agglomerative clusters according to their birth weight and duration of neonatal ventilation into the risk of subsequent viral infections [163]. This approach merits further study as it is possible that interventions such as iNO if delivered to a high-risk population might improve respiratory outcomes.

A number of strategies have been shown to reduce the incidence of BPD, but given its multifactorial nature, there is unlikely to be a single magic bullet to prevent BPD. It will be therefore important to investigate a combination of such strategies. In the meanwhile, it is important to introduce those preventative strategies without adverse effects into routine care such as caffeine and volume targeted ventilation (VTV) but with the appropriate VT levels. Other preventative strategies require further research before they should be introduced into routine care such as NAVA, stem cells and surfactant with budesonide. Stem cell administration has delivered promising results, but there are possible long-term adverse outcomes and therefore this needs particularly investigating.

Very few strategies have been robustly assessed in infants with evolving or established BPD. The growing number of BPD infants means this is now a crucial priority. Appropriate multicentre RCTs of novel modes of ventilation will be needed to establish the optimum mode of respiratory support for that population. It is now clear that many such babies have pulmonary hypertension and mandate that infants with evolving and established BPD should be routinely and regularly screened and the optimum treatment identified. Diuretics and bronchodilators are over-prescribed, and evidence-based guidelines need to be produced. Quality improvement projects will hopefully result in the appropriate use of diuretics, bronchodilators, and corticosteroids.

The chronic respiratory morbidity of infants who develop BPD and those with pulmonary hypoplasia, for example infants with congenital diaphragmatic hernia, means it is essential that it is the primary outcome rather than BPD or survival without BPD. Funders of randomized trials need to be further persuaded of the importance of this outcome. Equally, it will be important to define chronic respiratory morbidity with regard to what matters to the infant, their parents and healthcare utilization.

Article highlights

BPD preventative strategies:

• There are a number of preventative strategies which have been shown in randomized trials to reduce BPD, and these include systemically administered corticosteroids, vitamin A, caffeine, and volume guarantee ventilation.

• Promising interventions or those where further evidence is required are surfactant administered with budesonide, LISA, inhaled nitric oxide (iNO), NAVA and stem cells.

Management of infants with evolving or established BPD:

• Should be screened for pulmonary hypertension.

• Systematic corticosteroids should only be considered in those who remain ventilator dependent on high pressures and oxygen levels who have made no progress over the first 2 weeks despite the absence of a patent ductus arteriosus (PDA) or infection.

• Diuretics should be given to those not tolerating standard fluid volumes with poor growth.

• Regular bronchodilators should only be given to those infants who have shown a positive response, i.e. a reduction in respiratory support.

Declaration of interest

A Greenough has held grants from various manufacturers (Abbott Laboratories, MedImmune) and ventilator manufacturers (SLE). A Greenough has received honoraria for giving lectures and advising various manufacturers (Abbott Laboratories, MedImmune) and ventilator manufacturers (SLE). A Greenough has received a non-conditional educational grant from SLE. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.