A physiology-based approach to the respiratory care of children with severe bronchopulmonary dysplasia

Introduction

Bronchopulmonary dysplasia (BPD), the chronic lung disease of infancy that follows preterm birth, was first characterized by Northway and colleagues over 50 years ago. In that era, prematurity-associated lung disease contributed to high mortality (60%) in relatively late-gestation preterm infants by today’s standards (32–34 weeks gestation). Currently, survival for these moderate to late preterm infants is nearly 100%, with a 94% survival of preterm infants born even at 28 weeks gestation. ^, This remarkable success of modern care has increased survival of even the most extremely low gestational age newborns at the limits of viability (currently 22–23 weeks gestation), which likely accounts for the increasing rate of BPD in preterm infants born below 29 weeks gestation. As a result, BPD remains the most common morbidity of preterm birth, occurring in an estimated 10 to 15,000 infants per year in the United States alone. This has important health care implications, as infants with BPD require prolonged NICU hospitalizations; frequent readmissions for respiratory infections, wheezing, and related problems; and often have persistent lung function abnormalities and exercise intolerance as adolescents and young adults.

The overall incidence of BPD has increased over the last 10 to 20 years. However, most infants with chronic lung disease after preterm birth now have a different clinical course and pathology from that described by Northway and that was observed in infants dying with BPD during the presurfactant era. ^{, , ,} The classic progressive stages of disease, including prominent fibroproliferative changes, which first characterized BPD, are now just one phenotype of the disease that has been termed “old BPD.” The phenotype of “old BPD” is no longer the most common manifestation of BPD, the most common disease phenotype now is defined as a disruption of distal lung growth, which has been referred to as “the new BPD.” However, it is important to remember that both “old BPD” and “new BPD” are phenotypes still seen today. The “new BPD” phenotype can develop even in preterm newborns who have required minimal or even no ventilator support and relatively low inspired oxygen concentrations during the early postnatal days. ^, At autopsy, the lung histology of infants who die with “the new BPD” displays lung injury, but impaired alveolar and vascular growth are the most prominent findings. The “new BPD” is likely the result of disrupted antenatal and postnatal lung growth, which along with abnormalities of central and small airways causes persistent abnormalities of lung architecture and function. Long-term pulmonary outcomes in BPD are incompletely understood, but recent work suggests persistent high rates of abnormal lung function through late childhood to early adulthood. Indeed, recent studies have demonstrated that BPD is a risk factor for developing chronic obstructive pulmonary disease (COPD) in adults, ^, giving rise to the concept that BPD may be a novel COPD endotype.

Although improved care has generally led to milder respiratory courses, infants with BPD can still develop severe lung disease, as reflected by chronic respiratory failure with high mortality and related morbidities ( Fig. 14.1 ). The management of infants with sBPD has received less attention regarding clinical studies and interventions when compared with preventive strategies, yet these infants constitute a critical population who remain at high risk for extensive morbidities and late mortality. Therefore, the goal of this chapter is to characterize the epidemiology, pulmonary, and cardiovascular pathophysiology of sBPD, especially ventilator-dependent infants, and to discuss therapeutic strategies for their management based on best available evidence and/or the underlying physiology.

Definitions and scope of severe bronchopulmonary dysplasia

BPD has historically been defined by the presence of chronic respiratory signs, a persistent requirement for supplemental oxygen, and an abnormal chest radiograph at 1 month of age or at 36 weeks postmenstrual age (PMA) in patients born at <32 weeks gestation. This definition lacks specificity and fails to account for important clinical distinctions related to the extremes of prematurity and wide variability in how clinicians use prolonged oxygen therapy. The need for supplemental oxygen at 1 month in infants born at 24 or 25 weeks gestation may represent lung or respiratory control immaturity and not reflect the results of “lung injury,” and such infants may or may not develop chronic respiratory disease. A National Institutes of Health (NIH) sponsored conference in 2000 led to a definition of BPD that categorizes the severity of BPD according to the level of respiratory support required at 36 weeks PMA, which has been widely used in the literature. An advantage of this classification is that BPD is defined as a spectrum of disease and may be predictive of long-term pulmonary morbidity. The NIH grading system, however, does not account for newer methods of respiratory support for neonates, like the use of high-flow nasal cannula (HFNC) or more aggressive use of noninvasive ventilation with or without supplemental oxygen. Past studies suggest that this grading of BPD severity is associated with the degree of abnormal lung function during infancy ; however, recent studies suggest that antenatal factors are key determinants for late respiratory disease independent of the diagnosis of BPD. With the advent of newer therapies and approaches to respiratory support, the NIH system is also less able to predict mortality and important morbidities accurately.

Another approach to determine the severity of BPD is to assess chest radiographs, but for many infants with chronic supplemental oxygen dependency, the chest x-ray only demonstrates small volumes with hazy lung fields. Various scoring systems have been developed and may predict chronic oxygen dependency and troublesome respiratory symptoms at follow-up. ^, Further work is clearly needed to identify early physiologic, structural, and genetic or biochemical markers of BPD that are predictive of critical long-term endpoints, such as the presence of late respiratory disease evidenced by prolonged mechanical ventilation and oxygen therapy, recurrent hospitalizations, wheezing, respiratory medications, and/or exercise intolerance during childhood.

The original NIH classification system defines sBPD as the need for supplemental oxygen with an FiO ₂ ≥0.30 with or without positive pressure respiratory support at 36 weeks PMA in patients born at <32 weeks gestation. Using the NIH criteria, studies from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network and The Children’s Hospitals Neonatal Consortium described a 16% incidence of sBPD among infants born < 32 weeks gestation, ^, but this proportion can vary based on the definition of sBPD used. Of note, early respiratory deaths after the first week of life but prior to 36 weeks PMA may represent the most severe form of BPD yet are not typically included in databases since they fail to reach the standard endpoint.

In addition, the NIH classification system’s designation of sBPD pertained both to those infants who merely required supplemental oxygen ≥0.30 FiO ₂ and to those infants who continued to require invasive mechanical ventilation. To help distinguish the latter infants from others with sBPD, members of the BPD Collaborative proposed a refinement to the NIH classification, designating those infants born <32 weeks GA who were treated with supplemental oxygen for at least 28 days and who required FiO ₂ ≥0.30, or nasal constant positive airway pressure (nCPAP) or HFNC at ≥36 weeks as having type 1 sBPD, and those who required invasive mechanical ventilation at ≥36 weeks as having type 2 sBPD. Thus, the proportion of infants with the most severe disease requiring high levels of respiratory support have only recently been explored and optimal approaches to their care are incompletely understood. This is an important issue as mortality may increase with the duration of mechanical ventilation.

Recognizing similar shortcomings to the original classification, the NIH convened an expert panel whose workshop publication in 2018 suggested changing the severity of BPD from mild, moderate, and severe, to Grade I, Grade II, Grade III, and Grade III(A). In this classification, infants born <32 weeks GA who have clinical and radiographic evidence of parenchymal lung disease are assessed at 36 weeks PMA for the type of respiratory support required: those with Grade I disease require noninvasive ventilation or HFNC ≥3 LPM but no supplemental oxygen, or lower flow oxygen with FiO ₂ ranging from 0.22 to 0.79, depending on the flow of gas. Those with Grade II could be treated with invasive mechanical ventilation as long as they do not require supplemental oxygen, use noninvasive ventilation with supplemental oxygen <0.30 FiO ₂ , or use supplemental oxygen ≥0.30 FiO ₂ if flow is 1 to <3 LPM or >0.70 FiO ₂ if flow is <1 LPM. Infants with Grade III BPD require either invasive mechanical ventilation with supplemental oxygen or noninvasive ventilation with ≥0.30 FiO ₂ , and those with Grade III(A) died between 14 days postnatal age and 36 weeks PMA from respiratory causes.

The need to categorize the severity of BPD is not only important for epidemiological purposes, but having a common definition can also help with the design of clinical trials aimed at those infants most likely to benefit from advanced therapies, help identify mechanisms of injury, or help clinicians predict longer term outcomes. Focusing on this last goal, members of the Canadian Neonatal Network evaluated several definitions of BPD being used for clinical and epidemiological studies focusing on pulmonary and neurodevelopmental outcomes at 18 to 21 months of age. They concluded that need for supplemental oxygen and/or respiratory support at 40 weeks PMA best predicted respiratory morbidity at 18 to 24 months. Once again, however, use of HFNC without supplemental oxygen or standard nasal cannula therapy using very low-flow rates resulted in some infants who could not be classified using this system.

More recently, members of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network applied 18 prespecified severity-graded BPD definitions to a population of 2677 very preterm infants. The definition that best predicted late death or serious respiratory morbidity at 18 to 26 months was independent of supplemental oxygen use at 36 weeks PMA. Instead, Grade 1 infants required any kind of nasal cannula therapy at a flow ≤2 LPM; Grade 2 infants required >2 LPM nasal cannula (HFNC) or noninvasive ventilation; and Grade 3 infants required invasive ventilation. This definition accurately predicted late death or serious respiratory morbidity in 81% of the infants studied, and late death or serious neurodevelopmental disability in 69%. Further, the incidence of late death or serious respiratory morbidity rose from 10% among those infants classified as not having BPD to 77% among those with Grade 3 BPD. These same criteria were subsequently retrospectively applied to 24,896 infants born between 22 and 29-6/7 weeks in the Vermont Oxford Network. In this group, 10% died before 36 weeks PMA and 49% did not develop BPD while 37% were classified as having either Grade 1 or Grade 2 BPD. Grade 3 BPD developed in 4% of the cohort. Late deaths before NICU discharge occurred in 1% of those infants who survived beyond 36 weeks PMA; among those, 62% carried a diagnosis of Grade 3 BPD, while 35% had either Grade 1 or Grade 2 BPD, and 3% did not have BPD. The frequency of all the evaluated neonatal morbidities increased with severity of BPD, so that they occurred 2 to 3 times more commonly among those with Grade 3 BPD compared with those with Grade 1 or 2 BPD, and more than 4 times as commonly as among those without BPD. Length of stay, supplemental oxygen use at discharge, and need for tracheostomy were all greatest in the infants classified with Grade 3 BPD.

Separately, several of the various grading systems have been compared within populations of extremely preterm infants. Applying the original NIH 2000 definition, the 2018 NIH Workshop refinement of the original definition, and the 2019 Neonatal Research Network (NRN) grading system to 2,380 extremely preterm infants in the Korean National Network, investigators sought to determine which system would best predict respiratory and neurodevelopmental impairments at 18 to 24 months and again at 3 years of age. The original 2000 NIH severity classification did not show any severity-related increased risk for respiratory, neurodevelopmental, or growth impairments. Both the refined NIH Workshop system and the NRN system showed severity-related increases in risk for those impairments at both 18 to 24 months and at 3 years of age, but they noted that the NRN system was easier to apply, given the lack of need to determine supplemental oxygen use at 36 weeks PMA or over the first 28 days of life.

Members of the Children’s Hospitals Neonatal Consortium performed another retrospective comparison of the 2018 NIH Workshop and 2019 NRN systems, along with that of the Canadian Neonatal Network among 4161 preterm infants in their network to assess short-term outcomes. All three systems demonstrated a significant severity-based increase in risk of in-hospital mortality or need for tracheostomy, even when gestational age, gender, and center were controlled. Once again, the NRN system was found to be the easiest to apply, and it also had the strongest discrimination of the three for poor short-term outcomes. Investigators from the BPD Collaborative applied their refinement of the original 2001 NIH classification to explore short-term outcomes among 584 infants in their registry. The risk for mortality among those infants with type 2 sBPD was significantly higher than for those with type 1 sBPD (RR 13.8, 95% CI 4.3–44.5, P <0.0001). The infants with type 2 sBPD also had a significantly greater risk for tracheostomy, gastrostomy, impaired growth, and greater use of inhaled bronchodilators and corticosteroids than those with type 1 sBPD. This classification aligned well with the NRN severity classification, but less well with the 2018 NIH Workshop classification for severe BPD. In addition, 6% of the cohort could not be classified by the 2018 NIH Workshop classification scheme because of unreliable FiO ₂ data at 36 weeks PMA.

Using an estimated incidence of sBPD of 16% for infants born at <32 weeks suggests that ∼13,000 patients develop sBPD annually in the United States alone. Epidemiologic data are limited, but estimates suggest that roughly 8000 children in the United States receive mechanical ventilation at home. Based on 2011 data from the state of Pennsylvania’s Ventilator Assisted Children’s Home Program, 36% of ventilator-dependent children were diagnosed with chronic lung disease: 77% of these specifically with the diagnosis of sBPD. From these data it can be extrapolated that ∼2000 infants and children with sBPD are dependent on mechanical ventilation at home in the United States.

Severe BPD is directly linked with worse long-term outcomes, such as need for rehospitalization, need for pulmonary medications, poor neurodevelopmental outcomes, need for home ventilation, and others. In one study, the incidence of cerebral palsy was 11% and 27% in those with mild and severe BPD, respectively. A report of patients cared for in the Comprehensive Center for BPD at Nationwide Children’s Hospital showed that 12% of patients with moderate BPD had cognitive scores on the Bayley Scales of Infant Development at 18 to 24 months of <70, while 15% of patients with severe BPD had cognitive scores <70.

Pathogenesis of severe bronchopulmonary dysplasia

Preterm infants are especially susceptible to lung injury from mechanical ventilation, oxidative stress, and inflammation due to the extreme structural and biochemical immaturity of the preterm lung. As Northway first observed, BPD has multifactorial etiologies, including hyperoxia, ventilator-induced lung injury, inflammation, and infection. Animal studies suggest that lung injury due to each of these adverse stimuli is at least partly mediated through increased oxidative stress that further augments inflammation, promotes lung injury, and impairs growth factor signaling pathways. ^, Antenatal factors, such as maternal smoking, chorioamnionitis, preeclampsia, and intrauterine growth restriction (IUGR), are clear contributing factors to the risk for BPD and perhaps its severity. ^, A recent longitudinal study of 587 preterm infants found that maternal smoking increased the risk for BPD twofold and was associated with prolonged mechanical ventilation and respiratory support during the NICU stay. In this study, preexisting maternal hypertension was associated with a twofold increase in odds for BPD. Further studies are needed to determine how different etiologic mechanisms alter the risk for BPD as well as its severity.

Among at-risk infants, the duration and approach to mechanical ventilation, including the use of high inspired oxygen, high peak inspiratory pressures, lower positive end-expiratory pressures (PEEPs), and higher ventilation rate, are also associated with BPD, relationships that could be causal or simply reflect the underlying severity of acute respiratory disease. Mechanical ventilation can induce lung injury through volutrauma, in which phasic stretch or overdistension of the lung can induce lung inflammation, permeability edema, and subsequent structural changes that mimic human BPD, even in the absence of high levels of supplemental oxygen. ^, Aggressive mechanical ventilation with hypocarbia has been associated with the development of BPD, as reports have shown an association between low PaCO ₂ levels and BPD development. High tidal volumes should be avoided both during mechanical ventilation in the early stages of respiratory distress syndrome (RDS) in the NICU and during resuscitation in the delivery room. Although small tidal volumes may reduce the risk for ventilator-induced lung injury in preterm infants, failure to recruit and maintain adequate functional residual capacity (FRC) even with low tidal volumes is injurious in experimental models. Despite some data suggesting that alternate strategies such as nCPAP and other noninvasive ventilation modes may reduce the risk for BPD, there remains striking center-to-center variability and meta-analysis has not shown uniform benefits.

The association of volutrauma with the development of BPD has led to the use of strategies such as permissive hypercapnia to minimize lung injury. Various ventilator devices and strategies have been assessed regarding their ability to reduce BPD. Meta-analysis of randomized trials has demonstrated that patient-triggered ventilation does not reduce the incidence of BPD but, if started in the recovery phase of RDS, it significantly shortens weaning from mechanical ventilation. The results of randomized trials of highfrequency oscillatory ventilation (HFOV) or high-frequency jet ventilation (HFJV) have been inconsistent. ^, Two large studies that incorporated prenatal steroid and surfactant replacement therapy yielded different results. In one, which restricted entry to very low-birth-weight infants with moderate-to-severe hypoxemic respiratory failure following surfactant administration, HFOV was associated with higher survival without BPD and shorter duration of ventilation. No substantial benefit or adverse effects of HFOV were found in the other study, however, which randomized premature infants (<29 weeks) within 1 hour of birth regardless of the degree of lung disease. An explanation for those conflicting results may be that in the current era that includes the use of modified conventional ventilation strategies, pulmonary benefit from HFOV may only be demonstrable in infants with moderate-to-severe disease. Clearly, the strategies applied for either conventional or HFOV are more important than the device itself. HFOV is frequently used as “rescue” therapy in premature newborns with severe respiratory failure despite treatment with exogenous surfactant and conventional ventilation. Whether such an approach reduces the risk to develop BPD or improves long-term outcomes requires additional investigation.

An optimal ventilation mode has not yet emerged to prevent BPD, but it is clear from physiological studies that tidal volumes and inspired oxygen concentrations should be reduced as low as possible to avoid hypocarbia, volutrauma, and oxygen toxicity, while applying strategies to optimize lung recruitment. Two meta-analyses suggest that volume-targeted ventilation reduces the duration of mechanical ventilation and reduces the incidence of BPD. ^, An alternative approach to reduce the risk of developing BPD has been to avoid intubation and mechanical ventilation by using early nCPAP. For example, the SUPPORT study found that patients who received early nCPAP without intubation and surfactant therapy had decreased need for intubation or postnatal corticosteroids for BPD, required fewer days of mechanical ventilation, and were more likely to be alive and free from the need for mechanical ventilation by 7 days of age. Many centers now minimize their use of mechanical ventilation, preferring nCPAP with or without administration of exogenous surfactant and report low incidences of BPD in high-risk infants. Since the risk for BPD is associated with the need for mechanical ventilation and centers that use less mechanical ventilation have a lower incidence of BPD, avoiding or minimizing mechanical ventilation during the early course of extreme prematurity may prevent BPD or lessen its severity. As discussed below, however, ventilator strategies during the early stages of respiratory distress are strikingly different from approaches needed to optimize gas exchange and treat chronic respiratory failure in the setting of established BPD.

Pathophysiology of severe bronchopulmonary dysplasia