KEY POINTS
- 1.
Minimally invasive surfactant therapy administered via a thin catheter is the most commonly studied less invasive surfactant administration strategy and has been shown to improve survival free of bronchopulmonary dysplasia (BPD).
- 2.
Compared with continuous positive airway pressure, nasal intermittent positive pressure ventilation (NIPPV) is a useful method to avoid respiratory failure or intubation or extubation failure. However, NIPPV does not improve death or BPD.
- 3.
Volume-targeted ventilation is superior to pressure-limited ventilation for short-term respiratory outcomes and for death or BPD.
- 4.
Compared with an oxygen saturation target of 85% to 89%, a target of 91% to 95% decreases the risk of death and necrotizing enterocolitis without increasing blindness in extremely preterm infants.
- 5.
The benefits and the risks of systemic postnatal steroids in neonates at high risk of BPD must be carefully evaluated by the clinician. The optimal dosage and duration of systemic corticosteroids are still under investigation.
- 6.
Inhaled corticosteroids are not associated with a significant reduction in BPD and might increase mortality. Combined with surfactant administration, inhaled corticosteroids might be an attractive strategy to reduce BPD.
- 7.
Intramuscular administration of vitamin A modestly reduces the incidence of BPD, but the concern by healthcare providers of repeated painful intramuscular administration has restricted its clinical use.
- 8.
Caffeine reduces the incidence of BPD with some long-term mid–school-age neurodevelopmental benefits compared with placebo in extremely preterm infants.
- 9.
Inhaled nitric oxide, diuretics, and bronchodilators have not shown effectiveness in reducing the risk of BPD.
Introduction
Bronchopulmonary dysplasia (BPD), a multifactorial disease affecting the normal sequence of lung growth, is one of the most frequent complications of prematurity. Approximately 40% of neonates born before 28 weeks’ gestation are affected by BPD. Despite improved neonatal intensive care unit therapies, the incidence of BPD has not significantly changed during the past two decades. , Survivors with BPD are at increased risk of adverse neurodevelopmental and pulmonary outcomes. Consequently, BPD remains a major challenge for neonatologists, and it is a priority to improve the care of and optimize the outcomes for children with BPD.
BPD was originally described more than 50 years ago as a severe pulmonary disease occurring after treatment with mechanical ventilation and high levels of oxygen in preterm neonates. The seminal report from Northway et al. in 1967 described a cohort of 32 preterm neonates born between 30 and 34 weeks’ gestation, of whom only 4 survived. Since this report, several changes in neonatal care have drastically improved the survival of preterm infants born at increasingly earlier stages of gestation. The originally described BPD disease, now coined “old” BPD ( Fig. 14.1 ), has been replaced largely by “new” BPD, which affects predominantly extremely preterm infants ( Table 14.1 ; Fig. 14.2 ).
| Old BPD a | New BPD b |
|---|---|
| CLINICAL Stage 1: Acute respiratory distress syndrome. Stage 2: Opaque lung fields with air bronchograms due to patchy atelectasis alternating with emphysema. Lung volume normal to low. Pulmonary edema due to shunt across the ductus arteriosus. Stage 3: Small radiolucent fields and streaky densities with early hyperinflation. Stage 4: Hyperinflated lungs with generalized cystic areas. | CLINICAL Disorder of lung development in premature infants born at a gestational age <28 weeks and birth weight <1000 g with persistent respiratory insufficiency. Distinct stages not well-defined. |
| PATHOLOGY Fewer alveoli develop after birth. Many areas of the lung show inflammation and scarring. The size of alveoli varies with areas of atelectasis and hyperinflation. Strands containing hypertrophied peribronchial smooth muscle, fibroblasts, and dense fibrotic strands. Perimucosal fibrosis. Inflammation marked by newly infiltrated macrophages and resident histiocytes, many of which are enlarged with engulfed lipids (foam cells). Tortuous lymphatics. Altered microvascular development. Early changes of pulmonary hypertension can be seen with vessels showing medial hypertrophy and elastin-rich degenerative-regenerative lesions. | PATHOLOGY Overall fewer alveoli. Alveolar size varies with areas of atelectasis and hyperinflation. Altered microvascular development. Early changes of pulmonary hypertension can be seen with vessels showing medial hypertrophy and elastin-rich degenerative-regenerative lesions. |
a Old BPD was seen in premature infants born at relatively later gestational ages who sustained lung injury related to barotrauma/volutrauma and infection; the most prominent histopathological changes were those of inflammation and scarring.
b New BPD most commonly occurs in extremely preterm infants born before 28 weeks gestational age, and the most prominent changes are those of inhibited alveolar development.
The etiology of BPD is multifactorial and results from the contribution of antenatal exposures and postnatal injuries, superimposed on an immature lung ( Figs. 14.3 and 14.4 ). The pathogenesis of “new” BPD is characterized by a highly immature lung (at the late canalicular and/or saccular stage of development) with abnormal alveoli and vascular development. , In the most severe cases, infants with BPD may develop pulmonary hypertension and pulmonary vascular disease. Computerized tomography typically shows heterogeneously hyperlucent lungs owing to foci of air-trapping. Coarse interstitial markings can be seen ( Fig. 14.5 ).
With evolving neonatal respiratory management and the increasing survival of preterm neonates during the past decades, several different definitions of BPD have emerged to better represent the population at risk. In 1988, BPD was defined by the use of oxygen at 36 weeks’ gestation. In 2000, a more comprehensive definition was suggested and included a separate definition for infants born at <32 weeks’ gestation versus at ≥32 weeks’ gestation and for levels of severity (mild, moderate, and severe) based on the amount of oxygen provided and/or the need for respiratory support. This definition was further changed to include an oxygen challenge test. More recently, it was suggested that defining BPD only at 40 weeks’ gestation might better predict pulmonary outcomes. In practice, the definition of BPD as the need for supplemental oxygen beyond 36 weeks’ gestation is the most commonly used. , Despite the best attempts at correctly defining BPD, the current definitions are simply based on the ventilation and/or oxygen treatment at a specific time point rather than including any pathophysiological or anatomic aspects of the disease. , The definition of BPD is an evolving concept, and it remains a challenge when used as an endpoint in evaluating preventive and therapeutic strategies. , Future definitions of BPD should attempt to include markers of severity of lung pathology or specific biomarkers that would potentially better standardize the disease and improve the prediction of long-term outcomes.
This chapter’s main focus is on strategies to prevent BPD, including recent respiratory support strategies and pharmacologic approaches (corticosteroids, vitamin A, caffeine, nitric oxide, diuretics, and bronchodilators). Unfortunately, none of these approaches has markedly decreased the incidence of BPD. New therapies, including stem cell–based therapies and insulinlike growth factor 1, are currently being studied and will be briefly discussed in this chapter.
Management
BPD is a multifactorial disease. Current approaches aim to use lung-protective c=ventilation strategies, combined with pharmacologic therapies to attenuate inflammation, promote lung repair, and stimulate respiratory drive.
Respiratory Support Strategies
Different ventilation strategies have been considered to prevent the development of lung injury and establishment of BPD. Table 14.2 summarizes recent respiratory support approaches studied in preterm infants.
| Approaches | Evidence |
|---|---|
| Sustained inflation | Three meta-analyses compared sustained inflation to intermittent PPV: no effect on BPD and/or death One large RCT (SAIL trial): increased mortality at <48 h in infants receiving sustained inflation; no effect on BPD or death |
| Surfactant | One meta-analysis compared prophylactic surfactant to routine stabilization on CPAP: reduction in BPD or death with early CPAP treatment |
| INSURE | Cochrane review compared INSURE to rescue surfactant: INSURE reduced mechanical ventilation and BPD Meta-analysis compared early INSURE with CPAP alone: no effect on BPD and/or death |
| MIST | One metanarrative review (10 studies—thin catheter administration evaluated in 6 studies): surfactant administration via thin catheter may be efficacious and safe One systematic review comparing MIST to standard surfactant administration: MIST was associated with reduction in death or BPD One systematic review comparing MIST to 6 other ventilation strategies: MIST was associated with the lowest likelihood of death or BPD |
| NEWER VENTILATION STRATEGIES | |
| NIPPV | Cochrane review compared early NIPPV with early CPAP: NIPPV decreased respiratory failure and intubation; no effect on BPD Cochrane review compared NIPPV with CPAP after extubation in preterm neonates: NIPPV decreased extubation failure; no effect on BPD or death One RCT compared NIPPV with CPAP in infants aged <30 weeks: no effect on BPD or death |
| Noninvasive HFV | One meta-analysis compared noninvasive HFV with CPAP: noninvasive HFV decreased intubation rate and improved CO 2 clearance |
| Volume-targeted ventilation | Cochrane review compared volume-targeted ventilation to pressure-limited ventilation: volume-targeted decreased death or BPD |
| Oxygen saturation target | One meta-analysis compared high (91%–95%) with low (85%–89%) Sp o 2 target in extremely preterm infants: no difference in death or disability; higher risk of death in lower target Sp o 2 group |
Sustained Inflation
Preclinical studies have demonstrated that sustained inflation (SI) at the onset of neonatal resuscitation improves lung inflation and produces a greater functional residual capacity without impairing the neonatal cardiovascular transition. , Subsequent to these studies, several randomized controlled trials (RCTs) compared SI to intermittent positive pressure ventilation (PPV) at the initiation of resuscitation. Three meta-analysis compared the efficacy of SI immediately after birth versus intermittent PPV and showed no improvement in the rate of BPD and/or death. One meta-analysis showed improvement in short-term respiratory outcomes of infants receiving SI, with a decrease in mechanical ventilation within 72 hours after birth. The studies included in the three meta-analyses used heterogeneous SI strategies (one to multiple SIs, for 5 to 20 seconds, with variable positive inspiratory pressure) in a population of preterm infants of varied gestational age.
Recently a large multicenter RCT (SAIL trial), not included in the previous meta-analysis, reported on the effect of SI versus intermittent PPV in a cohort of extremely preterm infants. The authors reported no difference in the outcome of death or BPD between the groups. However, the trial was stopped early due to increased mortality at less than 48 hours of life in infants receiving SI. Current evidence does not support the use of SI in the prevention of BPD and/or death.
Surfactant
Based on a meta-analysis of studies comparing prophylactic versus selective administration of surfactant in very preterm neonates, the prophylactic use of surfactant is no longer recommended. The meta-analysis included two studies designed to compare prophylactic surfactant treatment with early initiation of continuous positive airway pressure (CPAP) treatment and found an increased risk of BPD or death with the prophylactic administration of surfactant (2 trials; 1744 neonates; relative risk [RR], 1.12; 95% confidence interval [CI], 1.02–1.24).
Surfactant administration traditionally involves intubation and mechanical ventilation. Exposure to mechanical ventilation is associated with risk of volutrauma, barotrauma, and inflammatory responses, known as important risk factors for the development of BPD. As such, new techniques to administer surfactant while avoiding prolonged ventilation have been developed.
Intubate, Surfactant, Extubate
The intubate, surfactant, extubate (INSURE) approach involves intubation for early administration of surfactant followed by a brief period of mechanical ventilation and extubation to CPAP. A Cochrane review compared this approach to rescue administration of surfactant in preterm infants with respiratory distress syndrome and showed a decrease in mechanical ventilation and BPD. A meta-analysis of 9 trials with a total of 1551 preterm infants compared early INSURE with CPAP alone. The authors reported no benefits of early INSURE in the outcomes assessed, including BPD and/or death. However, the estimated RR favored early INSURE over CPAP alone (12% reduction in BPD and/or death; RR, 0.88; 95% CI, 0.76–1.02). Still, the need for premedication, the secondary effects, and the failure to extubate in a significant proportion of neonates led to the development of alternative techniques with noninvasive or minimally invasive administration of surfactant, with the goal to avoid intubation.
Minimally Invasive Surfactant Administration
Several minimally invasive surfactant administration techniques (MIST) have been described, including administration via (1) a thin catheter, (2) aerosol or nebulization, (3) a laryngeal mask airway, and (4) the pharyngeal airway. A metanarrative review was conducted in 2014 to assess the safety and efficacy of these techniques. It included 10 studies, 6 of which used a thin catheter for surfactant administration, which appears to be an efficacious and potentially safe technique. Other systematic reviews comparing different ventilation strategies also suggested that MIST with surfactant delivery via a thin catheter reduced the composite outcome of death or BPD at 36 weeks’ gestation. ,
Further RCTs of surfactant administration via less invasive methods are underway and will help clarify the short- and long-term benefits of this practice. These studies will also help identify the best technique, optimal patient selection, and adequate surfactant dosage.
Newer Ventilation Strategies
Newer noninvasive ventilation strategies have been developed to avoid endotracheal intubation and its associated complications.
Nasal Intermittent Positive Pressure Ventilation
Nasal intermittent positive pressure ventilation (NIPPV) has been studied extensively for a variety of neonatal disorders. A Cochrane review compared the efficacy of early NIPPV versus early CPAP in preterm infants and showed that NIPPV was associated with a reduction in respiratory failure and intubation but no reduction in BPD. Another Cochrane review compared NIPPV versus CPAP after extubation in preterm neonates. The analysis showed that NIPPV decreased the incidence of extubation failure but had no significant effect on BPD or death. To our knowledge, only one RCT comparing NIPPV versus CPAP restricted enrollment to neonates born before 30 weeks’ gestation and assessed BPD or death as the primary outcome. In this large, multicenter study, there was no difference in the incidence of death or BPD among patients assigned to the NIPPV or CPAP group.
Noninvasive High-Frequency Ventilation
Noninvasive high-frequency ventilation (HFV) has been suggested as a gentler and highly efficacious mode of ventilation for CO 2 clearance. Small observational studies previously showed potential benefits of noninvasive HFV over CPAP in preterm and term neonates. , Despite the limited evidence available, noninvasive HFV is already used clinically in some European neonatal intensive care units. A meta-analysis including eight RCTs involving 463 patients evaluated the safety and efficacy of noninvasive HFV. The authors showed that compared with nasal CPAP or biphasic nasal CPAP, noninvasive HFV was associated with a lower intubation rate (RR, 0.50; 95% CI, 0.36–0.70) and a more effective clearance of CO 2 (weighted mean difference, −4.61; 95% CI, −7.94 to −1.28). So far, available data are promising for the use of noninvasive HFV. However, larger trials with long-term safety data are required.
Volume-Targeted Ventilation
Mechanical ventilation remains an essential tool in the management of many preterm infants, especially those born before 29 weeks’ gestation. , Newer modes of mechanical ventilation have been associated with better lung protection. A volume-targeted ventilation strategy, in which a constant volume is delivered with each ventilator inflation, has been shown to be a safe and efficient approach. A recent Cochrane review showed that this ventilation strategy, compared with pressure-limited ventilation, was associated with a decrease in death or BPD (RR, 0.73; 95% CI, 0.59–0.89). Additionally, volume-targeted ventilation is associated with a decreased duration of mechanical ventilation and a reduction in pneumothorax, hypocapnia, and severe intraventricular hemorrhage.
Several other ventilation strategies including high-frequency ventilation and patient-triggered ventilation have been evaluated but failed to show a difference in the risk of death or BPD. ,
Oxygen Saturation Targets
The neonatal oxygen prospective meta-analysis (NeOProM) compared the impact of high (91%–95%) versus low (85%–89%) oxygen saturation (Spo 2 ) target ranges on death or major morbidities in extremely preterm infants. , The meta-analysis included 5 large, multicenter trials performed in different parts of the world (the United States, Australia, New Zealand, Canada, and the United Kingdom), which together enrolled 4965 infants. The authors showed no difference between the groups in death or disability at 18 to 24 months. However, although infants assigned to the group with lower target Spo 2 had a lower incidence of retinopathy of prematurity requiring treatment, they had a higher risk of death and necrotizing enterocolitis and no difference in blindness. The benefits also occurred in subgroups. Further studies could help determine whether the target should be modified according to postnatal ages, but data are insufficient to make changes based on postnatal ages, because the benefits observed in these trials occurred with the same saturation targets across all postnatal ages. Pending better additional data, a target oxygen saturation of 90% to 95% might be safer.
Pharmacologic Interventions
Several different medications have been investigated as potential therapies to prevent or treat BPD. These medications include corticosteroids, vitamin A, caffeine, inhaled nitric oxide, diuretics, and bronchodilators. As demonstrated in Fig. 14.4 , these therapies target potential disease mechanisms related to lung injury and BPD.
Corticosteroids
Inflammation is known as an important mediator in the development of BPD. The use of corticosteroids to reduce inflammation has been extensively investigated ( Table 14.3 ).
| Recommendation | |
|---|---|
| SYSTEMIC CORTICOSTEROIDS | |
| In the first 7 days of life | |
| Early dexamethasone | Not recommended Increase CP and combined outcome of death or CP , |
| Early low-dose hydrocortisone | To consider in selected population Increase survival without BPD , Risk of gastrointestinal perforation when used in association with indomethacin |
| After 7 days of life | |
| Late corticosteroids | To consider in selected population Cochrane review: late corticosteroids (dexamethasone or hydrocortisone) associated with a reduction in BPD, with no difference in death or CP Systematic review: in infants at higher risk of BPD, late corticosteroids associated with a reduction in death or CP , |
| Late hydrocortisone | Not recommended Multicenter RCT: 22-day course of hydrocortisone did not improve the composite outcome of death or BPD Multicenter RCT: 10-day course of hydrocortisone between day 14 and 28 did not improve survival without BPD |
| INHALED CORTICOSTEROIDS | |
| Inhaled corticosteroids | Not recommended Cochrane review: inhaled steroids is not superior to systemic steroids for preventing BPD or death in ventilated preterm neonates, with similar neurodevelopmental outcomes |
| Early inhaled corticosteroids | Not recommended Cochrane review to determine the impact of inhaled corticosteroids when initiated within the first 2 weeks of life: reduction in BPD or death, but questionable clinical relevance Multicenter RCT on long-term outcomes of inhaled budesonide: higher mortality in neonates who received budesonide |
| Combination of inhaled corticosteroids and surfactant | Not recommended; larger trials needed Meta-analysis (two studies) evaluating efficacy of budesonide-surfactant versus surfactant alone or no treatment: reduction in BPD in patients receiving budesonide with surfactant |
Systemic Corticosteroids in the First 7 Days of Life
Several studies have assessed early dexamethasone treatment (≤7 days) in preterm neonates. , Although early dexamethasone reduced the incidence of death or BPD (RR, 0.88; 95% CI, 0.83–0.93), it is associated with significant short-term side effects (hyperglycemia, hypertension, gastrointestinal hemorrhage, and gastrointestinal perforation). Importantly, cerebral palsy was significantly more common in infants treated with dexamethasone (RR, 1.42; 95% CI, 1.06–1.91). Given the potential adverse effects of dexamethasone treatment in the first week of life, it is not recommended for the prevention of BPD. ,
Because of the serious side effects associated with early dexamethasone treatment, researchers have investigated the role of low-dose hydrocortisone as an alternative. There is evidence that sicker preterm infants have relative adrenal insufficiency and therefore are unable to produce sufficient cortisol to control inflammation in case of critical illness. Prophylaxis of early adrenal insufficiency with low-dose hydrocortisone to prevent BPD has been studied in five RCTs. In 1999, Watterberg et al. first described the effect of early low-dose hydrocortisone in a randomized, placebo-controlled study of 40 mechanically ventilated extremely low birth weight infants. These authors showed an increased likelihood of survival without BPD in patients treated with hydrocortisone. More recently, Baud et al. conducted a multicenter RCT (PREMILOC) including 523 neonates born at less than 28 weeks’ gestation who received either low-dose hydrocortisone for 10 days or a placebo. In this study, the authors showed a significant increase in survival without BPD in the hydrocortisone group (60% versus 51% in the placebo group; odds ratio [OR], 1.48; 95% CI, 1.02–2.16; number needed to treat [NNT], 12). Similarly, an individual-patient-data meta-analysis that included 982 neonates showed that early low-dose hydrocortisone for 10 to 15 days improved survival without BPD at 36 weeks (OR, 1.45; 95% CI, 1.11–1.90). Importantly, when hydrocortisone is given in association with indomethacin, there is an increased risk of spontaneous gastrointestinal perforation. Additionally, although neonates exposed to hydrocortisone were more likely to develop late-onset sepsis, there were no negative effects on mortality or neurodevelopmental outcomes at 2 years of age.
In conclusion, based on the available evidence, low-dose hydrocortisone initiated early after birth appears safe when not associated with indomethacin and improves survival without BPD, without having a negative impact on early neurodevelopment assessed at 2 years of age. As suggested by Doyle et al. in a recent Cochrane review, longer-term neurodevelopmental follow-up is needed to assess effects of hydrocortisone on higher-order neurologic functions. There is also a need to identify the patients who will benefit the most from this therapy. In its policy statement, reaffirmed in 2014, the American Academy of Pediatrics stated that early treatment with hydrocortisone may be beneficial in a selected population, but there is insufficient evidence to recommend its use for all neonates at risk of BPD.
Systemic Corticosteroids After 7 Days of Life
In a Cochrane systematic review updated in 2017, Doyle et al. examined the effects of late (>7 days after birth) systemic postnatal corticosteroids for prevention of BPD in 1424 preterm neonates. Infants treated with late systemic corticosteroids (dexamethasone or hydrocortisone) had less incidence of BPD at 36 weeks’ gestation (RR, 0.77; 95% CI, 0.67–0.88). Benefits of late corticosteroids also included reductions in failure to extubate and to be discharged on home oxygen and less rescue corticosteroid treatment. Adverse effects included short-term side effects such as hyperglycemia and hypertension and an increase in severe retinopathy of prematurity (without increase in blindness). There was no difference in the combined outcome of death or cerebral palsy, although long-term developmental data were limited. Interestingly, a systematic review published in 2005 showed that in infants at higher risk of BPD, corticosteroid treatment was associated with a reduction in death or cerebral palsy. In an updated analysis by the same authors with data from 20 RCTs, the same relationship was observed with greater statistical significance. There is ongoing research to determine the ideal dose and duration of corticosteroid therapy. Marr et al. recently compared 42-day versus 9-day courses of dexamethasone in extremely preterm neonates at high risk of BPD. The authors showed that the prolonged course of dexamethasone was associated with improved short-term outcomes and an increased rate of survival without handicap at 7 years old (75% of children in the 42-day group had intact survival at school age, versus 35% in the 9-day group; P < .005). Based on the available evidence, dexamethasone treatment may be considered in ventilator-dependent preterm infants at high risk of BPD.
Hydrocortisone has also been considered as an alternative to dexamethasone. A multicenter RCT (STOP-BPD) examined the effect of hydrocortisone initiated 7 to 14 days after birth on mortality or BPD among ventilated preterm neonates. The 22-day course of hydrocortisone (with a starting dosage of 5 mg/kg/day, for a cumulative dose of 72.5 mg/kg) did not improve the composite outcome of death or BPD at 36 weeks’ gestation (adjusted OR, 0.87; 95% CI, 0.54–1.38). More recently, a large multicenter RCT involving 800 infants born less than 30 weeks’ gestation at high risk for BPD evaluated the efficacy of hydrocortisone initiated after 2 weeks of life on survival without BPD. In this trial, hydrocortisone, started between postnatal day 14 to 28, was given over a period of 10 days (with a starting dosage of 4 mg/kg/day). This intervention was not associated with an improvement in survival without BPD, nor with survival without neurodevelopmental impairment.
Inhaled Corticosteroids
Inhaled corticosteroids were investigated as a possibly safer alternative to systemic corticosteroids. Unfortunately, the data regarding their efficacy are not convincing, and there are concerns regarding associated increases in mortality.
A Cochrane review including three trials (431 participants) compared inhaled with systemic steroids and showed that inhaled steroids did not confer any significant advantages over systemic steroids. Another Cochrane systematic review examined the effect of early (within the first 2 weeks) inhaled corticosteroids on BPD. Ten trials were included (with a total of 1644 very low birth weight [VLBW] infants), and the authors reported a significant reduction in the incidence of BPD or death in neonates receiving inhaled steroids (RR, 0.86; 95% CI, 0.75–0.99). However, this benefit is of questionable clinical relevance because the NNT for an additional beneficial outcome was 17, with a 95% CI of 9 to infinity. Importantly, a long-term follow-up study by Bassler et al. was not included in the review. Bassler et al. reported on the 18 to 22–month outcomes of a cohort of 863 extremely preterm infants randomized to receive early (≤24 hours) inhaled budesonide or placebo. They showed a significantly higher mortality rate in the budesonide group (19.9%) versus the placebo group (14.5%) (RR, 1.37; 95% CI, 1.01–1.86). Although inhaled steroids are associated with a reduction in BPD, the increased mortality reported in a large RCT of inhaled steroids for BPD prevention is worrisome. Thus inhaled steroids should not be routinely used in the care of preterm infants.
Inhaled corticosteroids administered in combination with surfactant has also been studied as a BPD prevention strategy. A meta-analysis of 2 studies including 381 VLBW infants with severe respiratory distress syndrome requiring mechanical ventilation with a high fraction of inspired oxygen reported a 43% reduction in the risk of BPD (RR, 0.57; 95% CI, 0.43–0.76; NNT, 5) with no difference in mortality. The major limitation of these studies is the high incidence of BPD in the control group (50%). The effect size in a cohort with lower incidence of BPD would likely be much lower. Larger trials are ongoing to determine the effect of budesonide-surfactant (NCT04019106, NCT02907593, NCT03275415, and NCT00883532).
Vitamin A
Vitamin A is an essential nutrient for lung development and for maintaining the integrity of the respiratory epithelium. As such, it has been examined as a potential way to prevent BPD. A meta-analysis showed that intramuscular administration of vitamin A in VLBW infants was associated with a modest reduction in the incidence of BPD (RR, 0.87 [95% CI, 0.77–0.99]; NNT, 11 [95% CI, 6–100]). However, vitamin A is not routinely used in practice, mainly because it involves repeated intramuscular injections, a painful procedure, and because of limited access and a perception of limited efficacy. Additional research has focused on determining the optimal dose and route of administration.
Caffeine
Caffeine is a methylxanthine widely used in neonatal care to prevent and treat apnea of prematurity. Caffeine acts by increasing minute ventilation, central sensitivity to CO 2 , and respiratory muscle function. The Caffeine for Apnea of Prematurity (CAP) trial showed that caffeine therapy, initiated in the first 10 days of life in VLBW neonates, was associated with a reduced risk of BPD (RR, 0.72; 95% CI, 0.58–0.89) and earlier discontinuation of positive airway ventilation and supplemental oxygen compared with placebo. A recent study from the Canadian Neonatal Network showed that earlier initiation of caffeine (in the first 2 days after birth) had additional benefits because it was associated with a decreased risk of death or BPD (adjusted OR, 0.81; 95% CI, 0.67–0.98). The 11-year follow-up study of the CAP trial showed that caffeine was safe, and although it did not improve functional outcomes, it was associated with a lower risk of motor impairment and improved visual-motor integration. , In summary, caffeine therapy for apnea of prematurity appears to be a safe and effective strategy to reduce the incidence of BPD in VLBW neonates.
Inhaled Nitric Oxide
Inhaled nitric oxide (iNO) is a pulmonary vasodilator currently used in term and near-term infants with pulmonary hypertension. Trials in preterm neonates were initiated after animal studies suggested that iNO could also have beneficial effects on lung injury and evolving BPD.
Two published meta-analyses evaluated the impact of iNO in preterm infants on the rate of BPD and mortality. , First, Donohue et al. included 14 RCTs in their analysis and showed a small reduction in the composite outcome of death or BPD (RR, 0.93; 95% CI, 0.87–0.99) but no difference in death alone or BPD. Second, a 2017 Cochrane review reported on 17 RCTs of iNO therapy in preterm infants, which were analyzed in three different categories based on their inclusion criteria. Eight trials of early rescue treatment (iNO initiated before 3 days) showed no significant effect of iNO on BPD or mortality. Similarly, four studies using routine prophylactic use of iNO shortly after birth showed no benefit on BPD or mortality. Later treatment with iNO, used in infants at higher risk of BPD, also showed no significant reduction in BPD or death, but the effect size approached significance (RR, 0.92; 95% CI, 0.85–1.01).
A recent RCT from the Newborns Treated with Nitric Oxide Trial Group, not included in the two meta-analyses discussed in the previous paragraph, studied the impact of iNO on the rate of survival without BPD. In a cohort of 451 preterm infants born before 30 weeks’ gestation and requiring positive pressure ventilation support on postnatal day 5 to 14, infants were randomized to receive iNO or placebo for 24 days. The authors showed that iNO was not associated with improved survival without BPD or neurodevelopmental outcomes at 18 to 24 months.
In conclusion, current evidence does not support the use of iNO in preterm infants to improve survival without BPD. , Current investigations into detecting early pulmonary vascular disease in preterm infants may open new therapeutic avenues for iNO or other targeted approaches.
Diuretics
Although diuretic therapy is frequently used to alleviate symptoms of BPD, there is only very limited evidence to support its use. Most trials have shown that diuretics may improve short-term pulmonary outcomes. However, there is no convincing evidence that the long-term use of diuretics (loop and thiazide diuretics) may improve important clinical outcomes such as BPD, duration of ventilation, or survival. ,
Bronchodilators
There is very little evidence about the role of bronchodilators in preventing BPD. One RCT studied inhaled salbutamol in ventilated preterm neonates and showed no effect on survival and/or BPD. A posthoc analysis from the Neonatal European Study of Inhaled Steroids compared outcomes of preterm infants who received early bronchodilators versus no bronchodilators and showed no effect on BPD and/or death. A systematic review investigating the role of bronchodilators in BPD concluded that there are insufficient data for a reliable assessment of this intervention.
New Therapies
Stem Cell Therapies
Stem cell–based therapies are emerging as a potential therapeutic strategy for several neonatal diseases including brain injury and BPD. Evidence suggests that impaired function and/or loss of stem/progenitor cell populations contributes to abnormal organ development/repair. , Mesenchymal stromal cells (MSCs), originally identified as niche cells for hematopoietic stem cells in the bone marrow, have been investigated as a potential therapy for BPD in several preclinical studies. A meta-analysis including 25 studies showed significant therapeutic benefits of MSCs in rodent models of BPD. MSCs exert their effect via a paracrine mechanism, which may explain their pleiotropic therapeutic potential (antiinflammatory, antifibrotic, and antioxidative).
Early-phase clinical trials investigating the feasibility and safety of MSC therapy for BPD are currently underway. A phase 1 trial conducted in South Korea included nine ventilated preterm infants who received a single intratracheal administration of allogeneic, cord blood–derived MSCs. The procedure was feasible and well tolerated, and the patients had no adverse effects on their growth, respiratory, or neurodevelopmental outcomes at 2 years. , A second phase 1 trial with a similar trial design, conducted with the same proprietary cell product in the United States in 12 preterm infants, confirmed feasibility and showed no short-term toxicity. A phase 1 trial of a single intravenous administration of human amnion epithelial cells in six preterm, ventilator-dependent infants at 36 weeks’ corrected age showed feasibility and absence of toxicity of this cell-based therapy approach. Although stem cell–based therapies have entered the clinical arena based on promising preclinical data, much more needs to be learned about the biology of these putative repair cells. Further research is needed to determine the optimal cell product, source, dosage, route, and timing of administration.
Insulinlike Growth Factor 1
Insulinlike growth factor 1 (IGF-I) is an essential fetal growth factor that increases during gestation. Preterm delivery is associated with a decrease in IGF-1 levels. Low IGF-1 circulatory concentrations in extremely preterm infants have been associated with BPD, retinopathy of prematurity (ROP), poor weight gain, and abnormal brain growth. A phase 2 RCT investigating the role of IGF-1 for the prevention of ROP did not demonstrate benefits in reducing severe ROP but found a decreased incidence of severe BPD, a secondary endpoint. Another phase 2 trial assessing IGF-1 in the prevention of BPD is currently ongoing (NCT03253263).
Long-Term Outcomes
BPD is well recognized as a major risk factor for lifelong respiratory and neurologic impairment. Survivors with BPD are described as having global dysfunction, affecting their motor, cognitive, language, and academic abilities. Children with BPD also have worse respiratory function, an increased need for respiratory medications, and a higher rehospitalization rate in their first 2 years of life. ,
Studies assessing respiratory function of adult survivors of BPD report more respiratory symptoms, impaired exercise capacity, and abnormal pulmonary function. Emphysema, a lung disease characterized by the destruction of alveolar capillary units that is usually described in the aging population, is reported as one of the most common computed tomography findings in adult survivors of BPD. Additionally, studies on adolescents and young adults born preterm have shown a significant increased risk for the development of pulmonary vascular disease and right ventricular dysfunction. These limitations may contribute to the development of other chronic conditions known to be associated with prematurity, including obesity, hypertension, diabetes, and cardiovascular disease.
The significant consequences of BPD underline the urgent need for transformative therapies and effective early intervention to prevent long-term complications.
Conclusion
Despite advances in neonatal care, BPD remains a frequent complication of extreme prematurity associated with mortality and long-term disability. Incremental progress has had only modest impact on the incidence of BPD as more and more extremely premature infants survive. Given the complexity of the pathophysiology of BPD, it is unlikely that a single therapy will substantially impact the disease. Instead, a combination of strategies targeting different disease mechanisms, both in the prenatal and postnatal periods, is more likely to be successful.
In parallel, there is a need to better understand normal lung development and the causal pathways involved in neonatal lung injury and the development of chronic lung disease in preterm infants. Disruptive new therapies such as stem cell–based approaches are currently being explored in preclinical studies and early clinical trials. Still, before implementing new therapies in the most fragile preterm population, several factors need to be considered, including solid preclinical evidence, well-designed clinical trials, and appropriate knowledge translation. Additionally, with the significant short- and long-term consequences of BPD, the impact of potential therapies should ideally be assessed longitudinally, with several years of respiratory and neurodevelopmental follow-up.
REFERENCES
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