Post–Neonatal Intensive Care Unit Management of Bronchopulmonary Dysplasia

CHAPTER 19

PosteNeonatal Intensive Care Unit Management of Bronchopulmonary Dysplasia JOSEPH M. COLLACO, MD, PHD • SHARON A. MCGRATH-MORROW, MD, MBA

INTRODUCTION Advancements in neonatal care have led to large numbers of extremely low-birth-weight infants surviving to discharge from the hospital. This in turn has led to an increasing number of infants and children with respiratory disease related to prematurity, requiring outpatient care. Symptoms may range from mild respiratory symptoms that resolve within weeks of discharge from the neonatal intensive care unit (NICU) to those requiring home mechanical ventilation for years. In this chapter, we describe the postNICU management of bronchopulmonary dysplasia (BPD), including medications, respiratory support, and preventing/treating common respiratory complications.

MEDICATIONS There are several different types of medications commonly encountered in outpatient clinical settings for former preterm infants, including inhaled b-agonists, inhaled and systemic corticosteroids, diuretics, and antipulmonary hypertensive agents. The efficacy of these medications in infants and children with BPD has not been rigorously studied, despite their common usage in this population. With the exception of antipulmonary hypertensive agents, there has been minimal change in the outpatient management of BPD in the past several decades.1 Most typically, administration of these medications is initiated during an infant’s initial NICU admission and is carried over into the outpatient setting upon discharge. Given the paucity of evidence for these medications’ use in both the inpatient and outpatient settings, it is likely that local inpatient practices dictate outpatient use leading to a significant variation. A snapshot study conducted in

2015 among eight tertiary care NICUs in the United States found significant variation in use for diuretics, inhaled corticosteroids, and inhaled b-agonists among infants diagnosed with severe BPD.2

INHALED b-AGONISTS Obstructive airway disease is a common manifestation of BPD and can present with signs and symptoms similar to asthma. Both airway inflammation and structural changes may play a role in the obstructive lung disease related to BPD. Compared with asthma, structural changes to the BPD airways may play a larger role in the pathogenesis of the disease.3,4 This dual physiology may give a picture of asthma partially responsive to standard asthma therapies based on the degree of airway inflammation versus structural changes present. The risk of childhood asthma may be 1.7e3.9 times higher in children with a history of BPD depending on gestational age at birth.5 However, the burden of the disease may be decreasing over time as a 2014 meta-analysis of cross-sectional data demonstrated that obstruction as measured by spirometry (forced expiratory volume in the first second of expiration [FEV1]) is becoming milder among preterm birth cohorts over the past several decades.6 Inhaled short-acting b-agonists (albuterol or levalbuterol) can be used as needed and/or as scheduled, ranging from daily to every 4 hours in an outpatient setting. Commonly, inhaled b-agonists are given as needed for acute respiratory symptoms such as wheezing, coughing, or unexplained tachypnea or work of breathing above baseline. Frequent use of or minimal responsiveness to short-acting b-agonists for chronic respiratory symptoms can occur with poorly controlled airway inflammation, bronchomalacia,

Updates on Neonatal Chronic Lung Disease. https://doi.org/10.1016/B978-0-323-68353-1.00019-1 Copyright © 2020 Elsevier Inc. All rights reserved.

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and/or recurrent aspiration. Airway inflammation may respond to controller medications, such as inhaled steroids; however in the absence of improvement, further diagnostic testing should be considered to rule out other causes of chronic respiratory symptoms such as anatomic or functional airway abnormalities and/or aspiration. Frequent use of short-acting b-agonists for acute symptoms, such as those that accompany a viral upper respiratory tract infection, should prompt evaluation by a medical provider and consideration for initiating a short course of systemic steroids. Scheduled inhaled b-agonists can be given for preventing the aforementioned symptoms in infants or children with severe symptoms or for airway clearance. In the case of the former, the goal would be to wean b-agonist use to an as-needed basis as soon as the patient will tolerate it. In terms of airway clearance, in addition to relaxing smooth airway muscles, b-agonists can increase ciliary beat frequency thus aiding in mucociliary clearance.7 Inhaled albuterol and levalbuterol are the most commonly used short-acting b-agonists in the United States; enteral preparations may be associated with significant cardiac side effects.8 Pediatric studies suggest that there is no difference in the degree of tachycardia resulting from albuterol use versus levalbuterol use,9,10 but there are no studies in preterm infants who have higher resting heart rates at baseline. There are also no published studies for the use of longacting b-agonists in preterm infants.

INHALED AND SYSTEMIC CORTICOSTEROIDS There is a role for the use of corticosteroids in the management of BPD as airway inflammation is associated with the development of BPD.11,12 Typically, inhaled corticosteroids are used as prophylactic medication to decrease chronic symptom burden and prevent acute exacerbations, whereas systemic steroids are more commonly used for treating acute exacerbations of respiratory symptoms that may be associated with respiratory infections, anesthesia, etc. Although there are a number of studies assessing the use of corticosteroids within the NICU, particularly for the prevention of BPD, there are fewer studies focused on outpatient outcomes in preterm infants. Several studies of inhaled corticosteroid use in the NICU have found no differences in neurodevelopmental disabilities at 1.5e3 years of age.13e15 Although one long-term study found an increase in mortality (relative risk, 1.37) primarily in the NICU setting among preterm infants receiving inhaled corticosteroids,13 other studies have not necessarily

observed this.14 A randomized controlled trial of inhaled corticosteroids in preterm infants with moderate-severe BPD reported in 2017, observed a trend toward reduced rehospitalizations and systemic steroid use over the 3 months following initial discharge.16 However, another randomized controlled trial of 30 infants with chronic lung disease reported in 2002 did not see a difference in respiratory symptoms, systemic steroid courses, or hospital readmissions over a 1-year follow-up period.17 There exists some evidence that adrenal suppression may occur in some children who are on inhaled corticosteroids,18 but this is not consistently seen.19 Given these mixed results, there is considerable variation in practice for the use of inhaled corticosteroids, ranging from 0% to 87% for infants with severe BPD among eight tertiary care centers in one snapshot study.2 Given the potential effects on both somatic growth and neurocognitive development,20 the use of systemic steroids is limited in the NICU, but systemic steroids may be helpful for acute management of respiratory exacerbations or for failure of weaning respiratory support (e.g., to aid with extubation) after NICU discharge. There may be a small subset of infants with severe BPD and chronic respiratory failure who are dependent on systemic corticosteroids to maintain stability, and these are the rare patients who may be discharged from the NICU setting on a daily or every other day systemic steroid dosing. In the outpatient setting, initiating inhaled corticosteroid use should be considered for chronic coughing/wheezing or frequent acute episodes of coughing/ wheezing that result in multiple systemic steroid courses, emergency department visits, or hospital readmissions. There may also be a lower threshold to consider these medications if a susceptible patient is likely to be exposed to multiple viruses (e.g., in daycare) or has a dysfunctional swallow associated with intermittent aspiration. The goal of management with steroids, inhaled or systemic, should always be to wean to the lowest possible dose while maintaining respiratory stability. The exact timing of weaning is dependent on a patient’s chronic symptoms and ability to handle acute exacerbations, as wheezing or asthmalike symptoms may continue to be present over the lifespan of a preterm individual21 or may improve within months to a few years after NICU discharge.22 Many patients will require a gradual step-down of therapies, particularly if adrenal suppression is present. The use of spirometry for children over 4 years of age may be helpful to follow obstructive lung disease and titrate the inhaled steroid

CHAPTER 19 dosing23 (see Table 19.1 for a list of useful diagnostic tests).

DIURETICS Among preterm infants with BPD, diuretics are frequently used to manage interstitial pulmonary edema secondary to increased capillary permeability.1 Within the NICU setting, there is limited published data demonstrating improvement of pulmonary mechanics with diuretics acting on the distal renal tubule,24 but data to support the sustained use of loop diuretics for management of BPD are not present.25 Although furosemide is commonly used in the NICU setting for time-limited courses,26 it is less commonly used for long-term use owing to its potential adverse events such as electrolyte disturbances and nephrocalcinosis. More commonly used for long-term

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management are the thiazide diuretics (chlorothiazide and hydrochlorothiazide) often in combination with spironolactone.1,26 They are associated with less electrolyte disturbances than furosemide and have been shown to improve respiratory mechanics and oxygen requirement in one randomized control trial of infants with BPD.1,27 As mentioned previously, there is significant variation in inpatient use of diuretics,2 which likely translates into variation in which outpatients are receiving diuretic therapy. There are no guidelines for when and how to wean diuretics in outpatients with BPD. A survey of pediatric pulmonologists found that approximately half of respondents would wean oxygen before diuretic use, and vice versa for the other half.28 In general, patients on home supplemental oxygen may wean from diuretic therapy at a later age than those not on supplemental oxygen.29 When weaning off diuretic therapy at

TABLE 19.1

Outpatient Diagnostic Testing for Preterm Lung Disease. Follow-up studies to be considered

Interventiona

Comments

• Spirometry

• Only for patients aged 4 years. A reduction in FEV1 may indicate the presence of small airway disease; a reduction in FVC may suggest exercise limitations. • Useful for screening for obstructive sleep apnea or titrating respiratory support. • May be useful in assessing for parenchymal disease/cystic disease, but it does involve radiation exposure. • Echocardiograms Can be used for screening for pulmonary hypertension or titration of therapies. Outpatient catheterization is typically reserved for procedural interventions or assessing pharmacotherapy failure. • May be useful in assessing for upper airway lesions and/or tracheobronchomalacia. In combination with observed feeding (FEES), it may be helpful in assessing dysphagia. • For older patients, they may be useful in assessing pulmonary reserve. Individual laboratories may have specific age/height criteria for completing studies.

• Overnight polysomnography • Chest computed tomography (contrast) • Echocardiography (cardiac catheterization)

• Airway endoscopy

• Exercise studies

FEES, fiberoptic endoscopic evaluation of swallowing; FEV1, forced expiratory volume in the first second of expiration; FVC, forced vital capacity. a The options presented in this table are not meant to be carried out for all patients, but are options that may or may not be pursued, given the individual patient presentations.

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home, families should be advised to monitor for oxygen desaturations if on home pulse oximetry, changes in respiration, and facial/peripheral edema.

ANTIPULMONARY HYPERTENSIVE MEDICATIONS

Supportive therapies should be considered as the firstline management of pulmonary hypertension associated with BPD, particularly if the pulmonary hypertension is mild or moderate. These may include the use of supplemental oxygen for pulmonary vasodilation, optimal nutrition to maximize lung growth, avoidance of aspiration and infection, and treatment of hemodynamically significant shunts/airway obstruction.30e32 Ideally, the decision to initiate antipulmonary hypertensive pharmacotherapy for a moderate to severe disease that does not respond to supportive therapies should be done in consultation with a multidisciplinary team with expertise in pulmonary hypertension.32 Although performing cardiac catheterization before initiating long-term pharmacotherapy has been recommended,33 in practice, many infants with BPD and pulmonary hypertension are at high risk for adverse outcomes with anesthesia and/or this procedure.30,34 It should be recognized that certain causes of pulmonary hypertension seen within the preterm infant population can be worsened with the initiation of antipulmonary hypertension therapy, including pulmonary vein stenosis, left ventricular dysfunction, certain intracardiac shunts, and/or collateral vessels.35 The most commonly used class of agents to treat pulmonary hypertension in patients with BPD is the selective phosphodiesterase type 5 (PDE5) inhibitors (most often, sildenafil). The evidence supporting its use is largely limited to retrospective single center studies.36e39 Potential adverse effects that may limit its use include transient hypotension, ventilationperfusion mismatch leading to desaturations, and priapism.36 Concerns have been raised regarding 3-year mortality with sildenafil in one randomized controlled trial of pediatric patients with pulmonary hypertension,40 but this has not been observed in other studies.41 Tadalafil has seen limited use at some centers, but there are no published data concerning its use in preterm infants. Two other classes of chronic antipulmonary hypertensive agents used with patients with severe pulmonary hypertension and BPD are endothelin receptor antagonists (bosentan) and prostacyclins (epoprostenol, iloprost, and treprostinil).35 Bosentan is administered orally and requires periodic transaminase

assessment owing to the risk of liver toxicity. The short half-life of prostacyclins makes effective delivery challenging; they are also associated with a risk of systemic hypotension.35 In preterm infants, epoprostenol and treprostinil have been administered via continuous intravenous infusion via central line, although treprostinil has also been administered via pump subcutaneously. Iloprost can be delivered via inhalation. Lastly, inhaled nitric oxide may be used in an inpatient setting for the treatment of acute pulmonary hypertensive crises.31,32

RESPIRATORY SUPPORT Oxygen Hypoxemia is a common manifestation of BPD. Owing to its sometimes slow resolution, many infants with BPD are discharged from NICUs on home supplemental oxygen typically delivered via nasal cannula. Flows may range from 1/32 L per minute (LPM) to 2 LPM and use may be continuous or intermittent (e.g., with feeding and/or sleeping only). Patients with moderate or severe BPD are more likely to be discharged on supplemental oxygen; a 2005 validation study of the NICHD BPD criteria in 4866 infants reported that 64.4% of patients with moderate or severe BPD were discharged to home on supplemental oxygen compared with 2.8% of their peers with no or mild BPD.42 In general, home supplemental oxygen can be discontinued for most infants with BPD before 12 months of age.43e47 The severity of BPD may be predictive of how long supplemental oxygen requirements will persist, as in the same study, infants with severe BPD were weaned from oxygen at a mean age of 9.7 months compared with their peers with milder disease who were weaned between 7 and 8 months of age on average.42 Age of being weaned off of oxygen has also been shown to be associated with the flow of oxygen prescribed at discharge with patients on higher flows requiring supplemental oxygen until a later age.43 There are no published guidelines or protocols for how and when to wean supplemental oxygen in the outpatient setting.28 Typically, pulse oximetry measurements are used to guide decision-making, although there is variation in the type of monitoring, ranging from single determinations in an outpatient clinic to providing a pulse oximeter in the home setting to the use of overnight polysomnography.43 It is important to recognize that daytime pulse oximetry alone may be misleading because saturations may be lower with sleep overnight, and even short pauses in breathing lasting a few seconds may lead to desaturations owing to

CHAPTER 19 decreased pulmonary reserve.48 There is no specific consensus regarding minimum acceptable oxygen saturation percentage, although a study of surveyed pulmonologists reported a range of values between 90% and 95%.28 Although nocturnal saturations are the primary data used for weaning decisions by most pulmonologists, other factors to be considered include somatic growth, other vital signs, recent hospitalizations, and echocardiographic data.28 There may also be a substantial fraction of parents (32.1%) who may undertake oxygen weaning without medical supervision, and in one study, unsupervised weaning was associated with pulmonary hypertension and public insurance.43

Tracheostomies and Home Mechanical Ventilation Patients with the most severe forms of BPD may require long-term ventilation for optimal growth and development. Estimates vary as to how many children with BPD are chronically ventilated, but the incidence may be 200 infants annually with as many as 2000 preterm infants and children with severe BPD in the United States requiring home ventilation at any one time.31,49,50 These patients typically have prolonged initial hospitalizations for months after birth for stabilization of respiratory status, managing other comorbidities, and coordinating care for discharge.51,52 Training of caregivers of patients with tracheostomies and ventilators is critical. Despite the use of monitoring devices, the risk of death is high, with a mortality rate of 18.6% among patients with BPD in one study.50 In one retrospective study of 228 children on home mechanical ventilation, the mortality rate was 21%, including 19% of deaths related to tracheostomy complications that were likely preventable.53 Factors that may contribute to these preventable deaths may include inadequate training of family and professional caregivers.49 The American Thoracic Society guidelines for pediatric patients on home mechanical ventilation recommend that they should be comanaged by a generalist and a respiratory subspecialist, have an alert and attentive caregiver at all times (in practice, this requires the use of home nurses for periods of time), and have two or more family members who are trained in all aspects of respiratory care.54 The guidelines outline the use of standardized discharge criteria and specific pieces of critical equipment. Currently, there are no published protocols for outpatient ventilator management of severe BPD, and ventilatory strategies may need to be personalized based on presenting needs. In contrast to the multiple

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modalities of ventilator support utilized in the NICU during various stages of evolving lung disease, most infants with BPD on home ventilators are on (1) synchronized intermittent mandatory ventilation (SIMV) mode with pressure control/pressure support, (2) continuous positive airway pressure (CPAP) mode with pressure support, or (3) CPAP only. Modes of ventilation incorporating volume control are less commonly used but may need to be considered for the most difficult-toventilate infants. For patients with established lung disease, lower rates and longer inspiratory times may promote more homogenous inflation of lung units with heterogeneous time constants due to cystic disease. For patients with significant tracheo- or bronchomalacia, a higher positive end-expiratory pressure (PEEP) may be required to maintain a patent airway. In such cases, direct visualization under flexible bronchoscopy can be useful in titrating ventilator pressures. While there are no published guidelines on the maximum acceptable fraction of inspired oxygen (FiO2) for discharge, maintaining FiO2 above 40% in the home setting is challenging owing to the amount of oxygen required. It is recommended to stabilize ventilator settings and oxygen requirements in an inpatient setting before the initial discharge. Compared with chronic respiratory failure requiring long-term ventilation, BPD has a more favorable prognosis, with many children able to wean off ventilator support as they age. Limited data suggest that the median age for weaning from ventilatory support is 2 years.50,55 Typically, ventilator weaning is conducted in an inpatient setting but may be considered with a more gradual approach in an outpatient setting with close monitoring. Essential elements for weaning ventilatory support include pulse oximetry, end-tidal CO2 monitoring, and frequent clinical assessments. In general, it is advisable to wean daytime support before weaning overnight support. Overnight polysomnography can be helpful in determining the safety of reduced ventilator support or whether adequate ventilation/ oxygenation occurs off of ventilator support. Even in patients who are unable to wean from ventilator support, repeat polysomnography should be considered every 12e36 months to reassess whether changes in settings are required. Caution is advised when weaning ventilator support for patients with BPD and pulmonary hypertension because the pulmonary hypertension may worsen or pulmonary hypertensive crises may occur with changes in gas exchange.30 Following weaning from mechanical ventilation, decannulation can be considered under supervision of a pediatric otolaryngologist, as preterm infants may

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also have airway anomalies (e.g., subglottic stenosis, granulomas) that require additional surgical management or preclude decannulation.55,56 The approach to decannulation varies among centers.55e57 Preparation and assessment for decannulation may include monitoring tolerance of downsized and/or capped tracheostomies. Typically, tolerance of capping is assessed overnight in an inpatient setting or with overnight polysomnography.55e57 Increased respiratory symptoms or events (e.g., increased work of breathing, desaturations, hypercarbia) or higher apnea/hypopnea indexes during polysomnography when the tracheostomy is capped are associated with a higher rate of unsuccessful decannulation.58,59 Decannulation should be planned during seasons when respiratory viruses are less frequent in the community; overnight inpatient observation should be strongly considered after decannulation as well.58

COMMON COMPLICATIONS AND THEIR MANAGEMENT (SEE TABLE 19.2) Respiratory Infections Perhaps one of the greatest sources of morbidity and mortality in preterm infants with BPD are respiratory infections, mostly viral. Up to half of infants and children are readmitted before 2 years of age after initial hospital discharge owing to respiratory illnesses.60,61

TABLE 19.2

Prevention of Common Complications. Intervention

Comments

• Preventing lung injury

• Avoidance of active smoking, secondhand smoke, air pollution • Prevention of (or mitigation of) aspiration

• Preventing infection

• Hand hygiene • Avoidance of sick contact • Influenza and pneumococcal vaccinations • Palivizumab prophylaxis

• Preventing pulmonary hypertensive crises

• Reducing the risk of respiratory infections • Preoperative anesthesia consults for pulmonary hypertension

While patients may present with typical symptoms associated with respiratory viral infections, such as cough and nasal congestion, among infants and children with BPD, wheezing and increased work of breathing are common. In more severe presentations, acute respiratory failure may occur. Some viruses are certainly associated with more severe presentations and mortality, such as respiratory syncytial virus,62 but it should be recognized that other common respiratory viruses, such as rhinovirus, can be associated with increased morbidities among patients with BPD.63 Patients with BPD may have longer recovery times from respiratory infections than their peers without BPD, and emerging evidence suggests that severe respiratory infections in infancy and early childhood may lead to altered lung function in childhood and adulthood.64e66 Management of respiratory infections typically involves close observation and supportive care. Escalation of respiratory support is common, including the use of supplemental oxygen, high-flow nasal cannulas, noninvasive/invasive ventilation, or positive pressure ventilation with intubation, depending on patient needs. Scheduled b-agonist therapies may aid with both small airway disease and mucociliary clearance. Courses of systemic corticosteroids should be considered to aid with the airway inflammation that is commonly present; patients may require tapering courses depending on recovery from symptoms and whether underlying adrenal insufficiency is present. Antibiotics are appropriate when bacterial disease is suspected or diagnosed. Pulmonary hypertensive crises may occur in infants/ children with a history of pulmonary hypertension (see the section Pulmonary Hypertension for additional description). Preventing respiratory infections or mitigating their severity is an essential part of BPD outpatient management. Avoidance of sick contacts should be encouraged when possible. Families should be aware that daycare attendance may result in higher risk of emergency department visits, systemic corticosteroid use, antibiotic use for respiratory illnesses, and days with difficulty breathing, likely secondary to an increased risk of acquiring respiratory viral infections in day care.67 Immunoprophylaxis (with palivizumab) for respiratory syncytial virus infection should be considered for high-risk infants.68 Some centers also recommend the 23-valent pneumococcal vaccination for children with BPD over 2 years of age, but there is no published data to support this practice. Lastly, exposure to secondhand smoke may increase the risk of acquiring respiratory infections in general69 and may be linked to an increased risk of hospital admission

CHAPTER 19 and activity limitations in infants and children with BPD.70

Pulmonary Hypertension Pulmonary hypertension is a complication of BPD, and although more commonly seen with more severe BPD, it can be observed with any severity of BPD.30,32 Few infants undergo the gold standard for the diagnosis of pulmonary hypertension (i.e., cardiac catheterization) owing to the risks of the procedure. In practice, echocardiography is used to diagnose the presence and severity of pulmonary hypertension, with severe pulmonary hypertension being associated with estimated pulmonary pressures >2/3 systemic pressures with severe ventricular septal flattening.32 Appropriate follow-up for preterm infants and children with pulmonary hypertension cannot be understated, as given the identical severity of BPD, pulmonary hypertension is associated with higher rates of morbidity and mortality.30,71e73 In the outpatient settings, echocardiography also serves as the primary means of serial assessment of pulmonary hypertension. The frequency of follow-up echocardiography is dependent on the stability of the patient and the weaning of respiratory support and antipulmonary hypertensive agents (every 1e4 months).32 Careful coordination between subspecialists weaning support and medications is essential to prevent pulmonary hypertensive crises. Limited prospective data demonstrates improvement of pulmonary hypertension over the first year of life.71 Long-term data from school-aged children with a history of BPD suggest that pulmonary hypertension does not persist even under pulmonary vasoconstrictive settings (i.e., hypoxia).74,75 Another study of 7-year-old children with a history of pulmonary hypertension found evidence of subclinical right ventricular dysfunction, but the significance of this is unclear.76 Pulmonary hypertensive crises represent an acute increase in pulmonary vascular pressures often accompanied by right-sided heart failure. Biomarkers of pulmonary hypertension may also demonstrate an acute increase from baseline (e.g., serum brain natriuretic peptide levels). These crises often occur in the setting of altered gas exchange such as surgery/anesthesia or respiratory infections30,34 or other scenarios where cardiac output does not meet metabolic demands, such as fever or hypovolemia. These crises may resolve with management of the offending event, but in some cases, they may require more aggressive management of pulmonary hypertension, including increasing doses of chronic therapy or the acute use of inhaled nitric oxide.32 Consultation with a team with

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expertise in pulmonary hypertension is essential, as crises may be fatal.31,32 More insidiously, ongoing aspiration may increase pulmonary hypertension severity over time. Therefore the presence of dysphagia and/or gastroesophageal reflux may require more aggressive medical or surgical management if pulmonary hypertension is present.30

Aspiration Aspiration of foreign materials into the upper and lower airways can have long-term consequences for the developing respiratory tract. For example, infants and toddlers who have a history of pneumonia confirmed by chest radiography have been observed to have worse lung function than those without pneumonia.65 Infants with BPD may be more at risk for aspiration, as they frequently have respiratory rates exceeding 60 breaths per minute, which may result in insufficient pharyngeal transit time for safe swallowing.77 Vocal cord paresis or paralysis may also be a risk for aspiration.78 Infants with BPD and severe intraventricular hemorrhages may also be at increased risk for dysphagia and aspiration, with one study reporting that infants with BPD and ventricular shunts were more likely to have gastric tubes placed.79 Common aspiration sources include aspiration during oral ingestion of liquids and/or solids, aspiration of oral and nasal secretions, and/or aspiration of gastric contents secondary to gastroesophageal reflux. Signs and symptoms of aspiration can vary between patients.80 Acute signs of aspiration may include choking, gagging, and coughing. Although oxygen desaturations can occur with aspiration while feeding, they may also be a sign of respiratory insufficiency with the exertion of feeding.81e83 Aspiration pneumonia or bronchitis may ensue within 24e72 h of a significant aspiration event. Chronic aspiration may present more insidiously than acute aspiration events, as symptoms do not always occur at the time of feeding. Although chronic symptoms may be similar to acute symptoms, their lack of temporal correlation to feeding can make them nonspecific. There is also a subset of infants with BPD that do not necessarily manifest any acute symptoms with aspiration, frequently referred to as “silent aspiration.”84,85 For these patients, chronic symptoms, worsening radiologic chronic findings, worsening pulmonary hypertension, or increased hypercarbia on serial blood gases may suggest that aspiration is occurring. Diagnosing aspiration frequently requires a tailored approach, including a careful history of respiratory and gastrointestinal symptoms, physical examination, observation of feeding within a clinical setting, and

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possible imaging or endoscopy. Standard imaging modalities such as chest radiography or computed tomography may demonstrate the sequelae of aspiration, although infiltrates secondary to acute aspiration may take up to 24 hours to be seen on radiography. Videofluoroscopic swallow studies can be used to diagnose aspiration secondary to oropharyngeal dysphagia, but they may overestimate the disease severity if a patient is not at his/her baseline respiratory status. Other imaging modalities to consider include upper gastrointestinal series and/or gastroesophageal scintigraphy (“milk scans”), which may or may not be diagnostic for aspiration secondary to gastroesophageal reflux.86 There are several types of endoscopy that may be helpful in diagnosing the cause and severity of aspiration in the respiratory and gastrointestinal tract. Flexible laryngoscopy and/or direct (rigid) laryngology/bronchoscopy of the upper airway performed by otolaryngologists can be used not only to diagnose upper airway anomalies (e.g., laryngeal clefts, vocal cord paresis) but also to characterize any upper airway inflammation secondary to gastroesophageal reflux. A specialized form of endoscopy during swallowing (fiberoptic endoscopic examination of swallowing) can be useful in characterizing the interactions between respiration and swallowing under direct visualization, but it does require trained providers.87,88 Flexible bronchoscopy of the lower airways, performed by pulmonologists, can assess for inflammatory changes secondary to aspiration (e.g., lower airway malacia) and perform bronchoalveolar lavage. Bronchoalveolar fluid can be submitted for both microbiologic studies to rule out infection and some specialized tests for aspiration such as histologic examination for lipid-laden macrophages. The lack of sensitivity and specificity regarding the relationship between lipid-laden macrophages and chronic aspiration however has questioned the utility of this test.89 Esophagogastroduodenoscopy performed by gastroenterologists can also assess for changes secondary to reflux and anatomic variants predisposing to reflux (e.g., hiatal hernia). The amount of aspiration that can be tolerated without an increase in acute illness or worsening of chronic disease is unclear90; however, infants and children with BPD may have more limited tolerance of aspiration, given their already reduced respiratory reserve. There are a number of interventions that should be considered for preventing aspiration. For aspiration secondary to oropharyngeal dysphagia, therapeutic options may include modifying feeding positions/ bottles/utensils or holding oral feeding altogether. In cases where NPO (nothing by mouth) status is

warranted, use of nasogastric tubes or gastrostomy tubes should be considered. The use of a nasogastric tube in the home setting for a patient with BPD is not advocated by some providers owing to the risk associated with a malpositioned tube in an infant who would poorly tolerate any aspiration.91 For aspiration secondary to gastroesophageal reflux, therapeutic options include restricting feeding volumes, using medications (i.e., histamine-2 blockers, motility agents, and/or proton pump inhibitors), and in the case of severe reflux considering the use of either postpyloric feeding tubes (i.e., nasoduodenal or nasojejunal feeding tubes, or jejunostomy) or surgical fundoplication. For aspiration of oral secretions, the mainstay of therapeutic options include decreasing secretions through pharmaceutical agents such as glycopyrrolate, scopolamine, inhaled ipratropium, and/or botulinum toxin injections.92e94 It should be noted that decreasing secretions may also result in increasing their viscosity leading to plugging of airways (or tracheostomies) with mucus. For decreasing existing inflammation from aspiration, inhaled corticosteroids can be considered, but there are no published data to support their use.

Obstructive Sleep Apnea Pediatric patients with a history of prematurity are at a higher risk of developing obstructive sleep apnea (OSA) than their full-term counterparts, including anatomic obstruction (e.g., relatively larger tongues, changes in palatal anatomy), acquired lesions (e.g., vocal cord paresis, subglottic narrowing), airway muscle hypotonia, and/or increased chest wall compliance.95e99 Even the common childhood cause for OSA, adenotonsillar hypertrophy, is observed more frequently among school-aged children with a history of prematurity.100 Regardless of the cause, OSA is more prevalent among patients with a history of prematurity, likely throughout their lifetimes, as it is more common on polysomnography in preterm infants101e104 and school-aged children.100 Additionally, young adults with a history of prematurity are more likely to chronically snore.105 It is important to diagnose and treat OSA, as untreated OSA may result in impaired somatic growth,106,107 may worsen neurocognitive outcomes,108,109 and may constitute a risk factor for pulmonary hypertension.110 Overnight polysomnography is considered the gold standard for the diagnosis of OSA, but it should be noted that not all sleep laboratories can accommodate infants or young children and that normative pediatric data for polysomnography is lacking; infants with BPD may be overdiagnosed with obstructive or central eventsowing to desaturations that

CHAPTER 19 may be due in part to poor pulmonary reserve.48 Although outcomes with commonly used therapies for OSA such as tonsillectomy/adenoidectomy or noninvasive positive pressure ventilation (i.e., CPAP or bilevel positive airway pressure [BiPAP]) have not been studied in pediatric patients with BPD, referral to an otolaryngologist or other respiratory specialists for the child diagnosed with OSA is recommended to determine treatment options.

CONCLUSIONS Respiratory disease in infancy can have consequences extending through the life span of the individual. Preterm infants with a history of BPD are at risk for asthmalike obstructive lung disease, OSA, exercise intolerance, and potential cardiovascular diseases associated with a history of pulmonary hypertension when compared with individuals born full term.111 Optimization of lung function and growth can be achieved through early diagnosis, or ideally, prevention, of complications. However, owing to the variable nature of preterm lung disease, a personalized approach to patients undertaken by providers familiar with BPD and its sequelae may be required.111

REFERENCES 1. Bhandari A, Panitch H. An update on the post-NICU discharge management of bronchopulmonary dysplasia. Semin Perinatol. 2018;42(7):471e477. 2. Guaman MC, Gien J, Baker CD, Zhang H, Austin ED, Collaco JM. Point prevalence, clinical characteristics, and treatment variation for infants with severe bronchopulmonary dysplasia. Am J Perinatol. 2015;32(10): 960e967. 3. Vom Hove M, Prenzel F, Uhlig HH, Robel-Tillig E. Pulmonary outcome in former preterm, very low birth weight children with bronchopulmonary dysplasia: a case-control follow-up at school age. J Pediatr. 2014; 164(1), 40-45 e44. 4. Baraldi E, Bonetto G, Zacchello F, Filippone M. Low exhaled nitric oxide in school-age children with bronchopulmonary dysplasia and airflow limitation. Am J Respir Crit Care Med. 2005;171(1):68e72. 5. Harju M, Keski-Nisula L, Georgiadis L, Raisanen S, Gissler M, Heinonen S. The burden of childhood asthma and late preterm and early term births. J Pediatr. 2014; 164(2), 295-299 e291. 6. Kotecha SJ, Edwards MO, Watkins WJ, et al. Effect of preterm birth on later FEV1: a systematic review and metaanalysis. Thorax. 2013;68(8):760e766. 7. Wong LB, Miller IF, Yeates DB. Stimulation of ciliary beat frequency by autonomic agonists: in vivo. J Appl Physiol. 1988;65(2):971e981.

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