Yan-Ping Xu · Li-Ping Shi · Li-Zhong Du

Bronchopulmonary dysplasia (BPD) is a chronic lung disease of premature infants that results from an imbalance between lung injury and repair in the developing lung [ 1].BPD is the most common respiratory morbidity with multiple factors implicated in its etiopathogenesis for preterm infants. Despite the scientific advances in the field of neonatology, the incidence of BPD has largely been unchanged due to increased survival of extremely premature infants.

Definition of BPD continues to be challenging and is used differently in the literature. BPD was first defined by Northway et al. [ 2] over 50 years ago; however, in 2001, the USA National Institute of Child Health and Human Development (NICHD) provided the following definition: if patients who are ＜ 32 weeks gestational age (GA) are assessed at 36 weeks postmenstrual age (PMA) or when discharged home, whichever comes first. Patients who are ≥ 32 weeks GA are assessed ＞ 28 days but ＜ 56 days PMA or when discharged home, whichever comes first. The severity of disease is graded “mild”, “moderate”, or “severe” at 36 weeks’PMA, or discharge for infants born at ＜ 32 weeks, or day of life (DOL) 56 for infants ≥ 32 weeks’ GA, according to the fraction of inspired oxygen level [ 3]. The 2018 NICHD Workshop proposed a new skeleton definition and a reclassification of severity based on modes of respiratory support grades (I, II, III and IIIA), which include a new category(IIIA) for early death (between 14 days of postnatal age and 36 weeks) owing to persistent parenchymal lung disease.The new mode of noninvasive ventilation was not included in the previous 2001 NICHD definition [ 4]. The 2019 Jenson’s study definition was a simplified version of the proposed 2018 revisions that depended only on the mode of respiratory support and not on the degree of oxygen supplementation [ 5].

Early respiratory management

BPD develops during the infant’s first several weeks and is influenced mainly by mechanical ventilation, excessive oxygen exposure and postnatal infections. Very low or extremely low preterm infants should start positive-end expiratory pressure (PEEP) and the establishment of functional residual capacity (FRC) as soon as possible in the delivery room if respiratory function is unstable. PEEP or continuous positive airway pressure (CPAP) can help premature infants establish stable FRC. Both are effective measures to avoid endotracheal intubation and to reduce the incidence of BPD. A multicenter RCT that compared to two sustained inflations at maximal peak pressure of 25 cm Hfor 15 seconds and used a T-piece with intermittent positive pressure ventilation in 426 extremely preterm infants showed increased mortality (7.4 vs 1.4%,respectively) at less than 48 hours of age. However, the rate of BPD at 36 weeks PMA did not differ between the groups [ 6]. High oxygen concentration during the resuscitation or early postnatal respiratory support is an independent risk factor for BPD. Thus, use of an initial FiOof 0.30 for babies ＜ 28 weeks' gestation, 0.21-0.30 for babies of 28-31 weeks, and 0.21 for those of 32 weeks and above is recommended in resuscitation. A suggested surfactant would be to treat babies who are worsening when FiO＞ 0.30 on CPAP pressure of at least 6 cm H[ 7]. In recent years, less invasive surfactant administration (LISA)or minimally invasive surfactant therapy (MIST) have been introduced gradually in clinical practice. There is evidence that LISA or MIST can reduce mortality or the incidence of BPD in premature infants [ 8, 9].

There are several options for noninvasive respiratory support, including CPAP, bi-level positive airway pressure(BiPAP), nasal intermittent positive pressure ventilation(NIPPV), nasal high frequency ventilation (NHFV) and high flow nasal cannula (HFNC). Individual studies do not demonstrate a significant risk reduction for the endpoint of BPD in preterm infants caused by early CPAP in respiratory distress syndrome (RDS) when compared to primary intubation [ 10].One meta-analysis comparing four studies found CPAP significantly reduces the risk of BPD or death [(relative risk: 0.91;95% confidence interval (0.84,0.99)] [ 11]. For preterm and very preterm infants, there is insufficient evidence to evaluate prophylactic CPAP (started within the first 15 minutes) compared to oxygen therapy and other supportive care. When compared to mechanical ventilation, prophylactic CPAP in very preterm infants reduces the incidence of BPD [ 12]. Compared with early CPAP, premature infants with early NIPPV had a lower need for endotracheal intubation, but the incidence of BPD did not decrease [ 13]. Another study showed that NIPPV did not result in a significantly lower incidence of intubation compared to CPAP in preterm twins with RDS [ 14]. A network meta-analysis that included 4078 neonates reported that NIPPV was more effective in decreasing the requirement of mechanical ventilation than CPAP [risk ratios (95% CI): 0.60(0.44, 0.77)]. NIPPV resulted in lower incidence of BPD or mortality when compared with CPAP [0.74 (0.52, 0.98)][ 15]. By comparing the effect of NIPPV and CPAP on respiratory support after ventilator withdrawal, NIPPV significantly reduced the rate of re-endotracheal intubation but failed to reduce the incidence of BPD [ 16]. However, Masry et al.found re-intubation rates were not statistically different with NIPPV when compared with CPAP [ 17]. HFNC has gradually gained popularity in recent years, but HFNC does not provide adequate PEEP owing to weak respiratory drive. Although HFNC is simple to operate and has less nasal mucosal damage than CPAP, there is no significant difference in the incidence of BPD [ 18]. HFNC is not recommend as the primary therapy for neonatal RDS compared to CPAP because HFNC resulted in a significantly higher rate of treatment failure than did CPAP[ 19]. For preterm infants with non-invasive respiratory support failure, tracheal intubation mechanical ventilation is required.Compared with pressure-limited ventilation (PLV), volumetargeted ventilation (VTV) can significantly shorten the duration of mechanical ventilation and can reduce the incidence of severe intraventricular hemorrhage, pneumothorax and BPD[ 20]. The preferred use of VTV over PLV is based on the systematic review of 1065 infants ventilated using VTV modes that had reduced rates of BPD or death compared with infants using PLV mode [ 20].

Early infection prevention

The consensus on whether chorioamnionitis increases the odds of developing BPD remains disputed because studies have failed to show consistently an association between chorioamnionitis and BPD [ 21, 22]. Perinatal

Ureaplasma

infection is associated with a variety of adverse pregnancy outcomes and neonatal diseases, including spontaneous preterm birth, clinical chorioamnionitis, congenital pneumonia,BPD, and death [ 23- 25]. Babies with

Ureaplasma

infection can produce a strong pro-inflammatory response in the lungs.

Ureaplasma

alone or with the combination of invasive ventilation can increase the risk of BPD. Whether treating

Ureasplasma

from the developing lung will reduce the risk for BPD is still unknown [ 26].

Hemodynamically significant patent ductus arteriosus management

Hemodynamically significant patent ductus arteriosus (hs-PDA) results in excessive pulmonary blood and pulmonary edema, which leads to up-regulation of oxygen demand and ventilator parameters and extends the duration of mechanical ventilation. Hs-PDA is diagnosed mainly by clinical symptoms and echocardiography. Echocardiographic evidence of hs-PDA meets one of the following criteria: ductal diameter ≥ 1.5 mm, unrestrictive pulsatile ductal flow(ductus arteriosus peak velocity ＜ 2.0 m/s), and left heart volume loading (e.g., left atrium to aortic ratio ＞ 1.5) [ 27].Whether exposure to an hs-PDA shunt increases the risks of BPD is still unclear. Sustained PDA exposure may contribute to BPD [ 28, 29]; however, an association between PDA and BPD has not been found in other studies [ 30, 31].A recent single center study found an association between BPD and exposure to a moderate to large PDA only when infants required mechanical ventilation and intubation for ≥ 10 days [ 32]. Persistent moderate-to-large PDA was not associated with an increased risk of BPD when the infant required ＜ 10 days of intubation [ 33]. HsPDA interventions include medical therapy and surgical ligation. Non-steroidal anti-inflammatory medicine, indomethacin and ibuprofen,are the drugs of choice. Currently, ibuprofen is used more commonly. The main adverse reactions are renal hypoperfusion, NEC and spontaneous intestinal perforation. Surgical ligation should be considered if hs-PDA cannot be closed after two courses of medical treatment or if contraindications of medical treatment exist.

Nutrition

BPD infants have a high incidence of extrauterine growth retardation owing to long-term increased work of breathing,restricted fluid intake, diuretics and glucocorticoid therapy.Malnutrition, in turn, hinders lung growth, development and repair, so adequate energy and nutrients intake is especially important. Amino acid and fatty acid metabolite profiles changed in infants with BPD after birth during the nutrition transitional period, suggesting that metabolic dysregulation may participate in the development of BPD [ 34]. Infants who developed BPD had a significantly lower amount of enteral nutrition during the first two weeks of life. However, the total intake of fluids, calories, amino acids, carbohydrates and weight gain per day was similar in infants with and without BPD [ 35]. Interestingly, a retrospective study enrolled infants born ＜ 28 weeks GA and showed that postnatal growth was better in infants diagnosed with BPD compared with infants without BPD possibly due to more aggressive nutrition strategies [ 36]. No studies have proven that fluid restriction is effective in the treatment of BPD, and excessive fluid restriction can lead to postnatal weight loss and can affect lung development [ 37].

Medications

Caffeine therapy for apnea of prematurity reduces the rate of BPD in infants with very low birth weight. In the trial 2006 infants with birth weights ranging from 500 to 1250 g during the first 10 days of life were randomly assigned to receive either caffeine or placebo. The infants who received caffeine experienced a 36% decrease in BPD at 36 weeks PMA compared with the controls [ 38]. Positive airway pressure was discontinued 1 week earlier in the infants assigned to caffeine [ 38]. Studies in recent years have shown also that early initiation of caffeine in the group of premature infants did not reduce the age of first successful extubation.A nonsignificant trend toward higher mortality in the early caffeine group led to a cautious decision to stop the trial[ 39]. However, in a large cohort study showed the use of early caffeine before 3 days after birth was associated with a decreased incidence of BPD compared with later use [ 40].The efficacy and safety of early caffeine prophylaxis in very low birth weight need to be determined. Therefore, more studies are needed to clarify the time and duration of caffeine application after birth.

The benefits of glucocorticoids on the respiratory system should be weighed against the risk of systemic adverse effects, including cerebral palsy (CP). The review supports the use of systemic corticosteroids for infants after 1 week of birth who cannot be weaned from mechanical ventilation. In one study dexamethasone probably reduces BPD at 36 weeks PMA, but hydrocortisone does not and both medicines without evidence of increased CP [ 41]. Meta-analysis showed that the use of dexamethasone at either high dose or low dose decreased the risk of BPD, and there were no statistically significant differences in the risk of CP between different corticosteroid doses [ 42]. Furthermore, there is no evidence that early inhaled steroids confer important advantages over systemic steroids in the management of ventilator dependent preterm infants [ 43].

Summary

As BPD has evolved for its definition, prevention, and management, this commentary briefly summarizes the current information on continuing interventions to reduce BPD based on recently published studies. The majority of single interventions tried thus far have not proven to be beneficial in rigorous meta-analyses of eligible studies. Ultimately,the most effective strategy for preventing BPD is to avoid extreme preterm birth. Mesenchymal stem/stromal cells have been investigated as a potential tool for preventing and treating BPD [ 44]. Here again, the safety and efficacy of cell therapy in BPD need further study.

Author contributions

XYP contributed to writing of original draft.SLP and DLZ contributed to revision and editing for the paper.

Funding

This work was supported by grants from the National Natural Science Foundation of China (No.81873845).

Data availability

Not applicable.

Declarations

Ethical approval

Not required.

Conflict of interest

No financial or non-financial conflict of interests have been received.