581CHAPTER 51 Neonatal Pulmonary Disease congenital heart lesion for which neonates may mistakenly be placed on ECMO A high index of diagnostic suspicion is war ranted in a term or near term infant wh[.]
CHAPTER 51 Neonatal Pulmonary Disease congenital heart lesion for which neonates may mistakenly be placed on ECMO A high index of diagnostic suspicion is warranted in a term or near-term infant who has a clinical and radiographic picture similar to surfactant-deficient respiratory distress or group B streptococcal sepsis 581 Low plasma bicarbonate represents a metabolic acidosis that may present as tachypnea and respiratory distress in the neonate, although it usually does not occur in isolation Of note, metabolic acidosis with a normal anion gap may be a feature of neonatal diabetes or may indicate bicarbonate loss via the kidneys or intestines Gastroenteritis, renal tubular acidosis, and mineralocorticoid insufficiency are common causes Differentiating the source of the acidosis is important because bicarbonate therapy may be harmful depending on the underlying problem survival at lower gestational ages and current respiratory management using selective exogenous surfactant and noninvasive ventilatory support, BPD is increasingly seen in extremely premature infants less than 28 weeks’ gestational age at birth.106 These newborns are more likely to display mild lung disease during the first few days of life and limited barotrauma and volutrauma Developmental arrest or delay in pulmonary and vascular maturation is thought to be primarily responsible for the “new” BPD in which histology shows minimal fibrosis but decreased alveolar divisions and arrested vascular development There may also be a genetic predisposition This contrasts with the postnatal insults causing structural lung injury, which were the main causes of “old” BPD in which there was emphysema and atelectasis, interstitial fibrosis, smooth muscle hyperplasia of the airways and pulmonary vessels, and right ventricular hypertrophy Bronchopulmonary dysplasia remains a clinical diagnosis that takes into account gestational age at birth, postnatal age, and need for supplemental oxygen and/or positive pressure ventilation Recognizing the changing spectrum of new BPD, in 2001 the National Institutes of Health (NIH) recommended definitions include severity classifications in terms of the need for supplemental oxygen and/or positive pressure ventilation at 36 weeks’ postmenstrual age107 (Table 51.1) They also recommended that chronic lung disease of prematurity (BPD) be distinguished from other forms of chronic lung disease diagnosed later in life (such as asthma or emphysema) Using the 2001 NIH BPD definition, an estimated 10,000 infants are diagnosed with severe BPD annually in the United States.108 The NIH has since suggested further refinements to the definition, which includes a grade system accounting for newer modes of noninvasive ventilation109 (Table 51.2) While these consensus definitions better describe the alveolar simplification components of BPD that manifest as impaired gas exchange (often resulting in hypoxemia and hypercarbia), they not well designate the additional vascular, airway, and lung function issues described beyond infancy in premature children with and without a diagnosis of BPD As such, BPD remains a surrogate diagnosis for longer-term chronic pulmonary insufficiency of prematurity.110 The pathogenesis of BPD is multifactorial and involves prolonged injury and repair of the still developing lung (Fig 51.2) Human lung development can be viewed as progressing through Neonatal Chronic Lung Disease of Prematurity: Bronchopulmonary Dysplasia TABLE Diagnostic Criteria for Bronchopulmonary 51.1 Dysplasia: National Institutes of Health, 2001 Metabolic Disorders Metabolic acidosis results in a compensatory respiratory alkalosis, which may manifest as respiratory distress For example, sepsis or perinatal asphyxia are included in this broad category in the presence or absence of lung disease Inborn errors of metabolism (IEM) are a heterogeneous group and are relatively rare Consequently, the possibility of an IEM may be overlooked Even in an era of expanded newborn screening in many US states and in several other countries, newborn screening results may be initially unavailable or require special expertise for interpretation An infant with an IEM that causes metabolic acidosis or metabolic encephalopathy may have deep and labored respirations (Kussmaul breathing) In many cases, the condition will rapidly progress to respiratory failure and apnea Other manifestations of IEM result either from accumulation of a toxic product or deficiency of an essential substrate In many IEMs, there may not be dysmorphic features, seizures, or vomiting Instead, there may be a pattern of worsening but nonspecific signs of multiple organ dysfunction that may not respond to routine intervention It is important to maintain a high index of suspicion for IEMs, especially when there are no identified risk factors for respiratory distress A delay in diagnosis and treatment can be catastrophic Intestinal or Renal Bicarbonate Wasting Intrauterine lung development is disrupted following premature birth, resulting in alveolar and vascular arrest with ongoing postnatal lung injury and repair Survivors of premature birth exhibit increased risk for respiratory disease and abnormal measures of lung function in childhood and early adulthood First described in 1967 by radiologist Dr William Northway and colleagues, bronchopulmonary dysplasia (BPD) defines the chronic lung disease associated with prematurity.105 Higher pressures (causing barotrauma), excessive tidal volumes (causing volutrauma), loss of functional residual capacity (causing atelectotrauma), high oxygen concentration (causing oxidative injury), and prolonged time on mechanical ventilation (causing airway trauma) all contribute to an increased risk of developing BPD In the initial Northway et al report,105 BPD survivors were all 30 weeks’ gestational age or older at birth and exogenous surfactant therapy was not yet available However, with improved SUPPLEMENTAL O2 FOR 28 DAYS AND ,32 weeks’ GA at birth 32 weeks’ GA at birth Mild BPD Room air at 36 weeks’ corrected GA or at discharge Room air at postnatal day 56 or at discharge Moderate BPD ,30% O2 at 36 weeks’ corrected GA or at discharge ,30% O2 at postnatal day 56 or at discharge Severe BPD 30% O2 and/or positive pressure at 36 weeks’ corrected GA or at discharge 30% O2 and/or positive pressure at postnatal day 56 or at discharge BPD, Bronchopulmonary dysplasia; GA, gestational age; O2, oxygen 582 S E C T I O N V Pediatric Critical Care: Pulmonary TABLE Refined Definition for Bronchopulmonary Dysplasia: National Institutes of Health, 2018a 51.2 Invasive Positive Pressure Noninvasive Positive Pressure (High NC flow 3 L/min) NC Flow to ,3 L/min Oxygen Hood NC Flow ,1 L/min Grade I — 21% 22%–29% 22%–29% 22%–70% Grade II 21% 22%–29% 30% 30% 70% Grade III 21% 30% — — — Grade III(A) Early death between 14 days and 36 weeks corrected GA attributable only to parenchymal lung disease and respiratory failure a Premature infant (,32 weeks’ GA at birth) with persistent parenchymal lung disease (confirmed by radiograph) on any of the following respiratory modalities AND corresponding O2 concentrations at 36 weeks’ corrected GA GA, Gestational age; NC, nasal cannula Multiple risk factors for BPD Antenatal factors Transitional factors Prematurity Initiation of positive pressure Genetics Growth restriction Male Oxygen Ventilation Sepsis & infection PPROM/chronic chorioamnionitis FETAL LUNG Preventive strategies Postnatal factors PREMATURE LUNG Noninvasive positive pressure, selective surfactant Methylxanthines, vitamin A, macrolides BPD LUNG Postnatal steroids, nutrition, diuretics • Fig 51.2 Multiple risk factors for bronchopulmonary dysplasia (BPD) Factors and exposures associated with increased risk for BPD during lung development (top, red) Risk mitigating strategies and treatments for BPD (bottom, green) PPROM, Preterm premature rupture of the membranes five stages Each stage is identified by the appearance, growth, and differentiation of various structures in the airways, parenchyma, and pulmonary vasculature Stage 1: Embyronic—budding of the foregut endodermal epithelium into adjacent primitive mesoderm Stage 2: Pseudoglandular—repeated dichotomous branching of epithelial-lined airways Stage 3: Canalicular—differentiation of alveolar cells in concert with proliferation of the pulmonary vasculature and epithelial thinning to form functional gas exchange units Stage 4: Saccular—additional branching and lengthening of the acinar tubules and buds to form thin-walled alveolar saccules and ducts Stage 5: Alveolar—extensive proliferation of the alveolar ducts and formation of alveoli and capillary units for efficient gas exchange The extremely premature infant at highest risk for BPD is bridging stages and at birth, with viability largely dictated by the presence of functional gas exchange units Accordingly, the incidence of BPD increases with severity of prematurity (Fig 51.3) It should be noted that intrauterine pulmonary development occurs under conditions of low oxygen tension and high pulmonary vascular resistance Under these hypoxic conditions, growth factors direct normal lung development and vascularization With premature birth, the immature lung is exposed to oxygen (even room air could be considered relative hyperoxia), which may lead to a decline in hypoxic growth factors (such as hypoxia-inducible factors, vascular endothelial growth factor, and platelet-derived growth factor) while factors that limit cell growth and alveolarization (such as transforming growth factors a and b, and connective tissue growth factor) are overexpressed, thereby arresting pulmonary development in stage 4.111 Infiltration of inflammatory cells and imbalances of multiple proinflammatory mediators (such as nuclear factor-kb, interleukins, and tumor necrosis factor-a) are associated with increased risk of BPD and have been linked to experimental BPD.112,113 The premature infant’s antiinflammatory and repair responses are modulated by genetic and perinatal exposures to volutrauma/ barotrauma, hyperoxia, pulmonary edema, and both prenatal and postnatal infection Additional risk factors include male sex, intrauterine growth restriction, and hemodynamically significant PDA Birth characteristics (gestational age, birthweight, sex, race) and respiratory parameters have been used to estimate postnatal risk for development and severity of BPD prior to 28 days of CHAPTER 51 Neonatal Pulmonary Disease Bronchopulmonary dysplasia by gestational age 100 Incidence (%) 80 60 40 20 22 23 24 25 26 27 28 29 Gestational age at birth (weeks completed) • Fig 51.3 Bronchopulmonary dysplasia (BPD) incidence by gestational age in weeks Diagnosis of BPD is inversely related to gestational age, with increased incidence at the earliest gestational age (BPD defined as use of supplemental oxygen at 36 weeks corrected gestational age or discharged/transferred on supplemental oxygen at 34 to 35 weeks corrected gestational age) (Data from Vermont Oxford Network Database of Very Low Birth Weight Infants Born in 2017 Burlington, VT: Vermont Oxford Network, 2019.) age.114 Early cumulative supplemental oxygen exposure and intermittent hypoxemia events have also shown associations with the diagnosis of BPD.115–117 In addition to the need for supplemental oxygen and/or positive pressure ventilation, the clinical features of BPD depend on the severity and extent of lung injury Infants with severe disease often require considerable oxygen and ventilator support beyond the first week of life and are slow to wean from support over weeks and months In the less severe and more common instances, infants may appear stable on minimal supplemental oxygen and ventilatory support during the first weeks of age with failure to wean or progressive need for increased support.118 Infants with established BPD often have tachypnea, chest retractions, and a hyperexpanded chest at baseline Auscultation will often reveal diffuse crackles, wheeze, or diminished breath sounds over dependent regions Hypoxemia, desaturations, bronchospasm, and compensated hypercarbia are also common Infants with severe BPD are at risk for pulmonary hypertension and varying degrees of right ventricular failure or, in less severe cases, simple fluid retention Chest radiograph findings of new BPD show diffuse coarse opacities with or without hyperinflation Recurrent pneumonias, aspiration, and growth failure may further complicate the postnatal course Likely due to their increased work of breathing, infants with BPD have increased caloric requirements (140–150 kcal/kg per day).119 Given a propensity for fluid overload, fortification and/or concentrated feeds are often necessary to prevent nutritional failure Feeding problems and oral aversion requiring prolonged nasogastric tube feeds are common; in some cases, gastrostomy tube placement is necessary Diuretic use may also require further electrolyte supplementation Inguinal hernias are also common complications due to delayed closure of the inguinal canals, raised intraabdominal pressure, and muscular weakness associated with suboptimal growth Pulmonary hypertension complications may be present in more than a quarter of infants with severe BPD,108 with a 50% 583 2-year mortality from diagnosis of suprasystemic pulmonary pressures.120 Risk factors include extreme prematurity, fetal growth restriction, oligohydramnios, and prolonged supplemental oxygen and ventilation requirements Disruption of vascular development results in a reduced cross-sectional area of vessels Arterial walls are thickened and are hyperresponsive to vasoconstriction Pulmonary arterial pressures normalize during childhood in most patients but may still be hyperreactive to hypoxic stress Treatment options for pulmonary hypertension include vasorelaxants such as supplemental oxygen, inhaled nitric oxide, sildenafil, bosentan, and prostacyclin analogs.121 In some cases, supplemental oxygen and home oximetry monitoring may be needed after hospital discharge With alveolarization continuing during the first years of life, most infants on home supplemental oxygen are able to be weaned off by their first birthday.108 Rarely is tracheostomy and chronic ventilation necessary for severe BPD alone.122 Among tracheostomized patients, approximately 60% will be decannulated before their sixth birthday, with a median age for liberation from ventilation of years and decannulation of years.123,124 Very-low-birthweight infants with BPD are at increased risk for neurodevelopmental impairments, including gross and fine motor skills as well as cognitive and language deficits.125 Premature infants diagnosed with BPD are often rehospitalized during the first years of life for respiratory exacerbations.126 Premature birth is associated with increased risk for wheezing disorders.127 Children and young adults born prematurely with BPD have a lower forced expired volume in second when compared with peers.125 While premature infants with BPD show improvements in FRC during early childhood,128 likely due to continued alveolarization and lung growth,129 airflow obstruction may worsen during adolescence in teens diagnosed with BPD during infancy.130,131 Deficits in spirometry and reduced exercise capacity are still consistently reported into early adulthood among BPD subjects.132,133 Likely due to increased survival of extremely premature newborns, static or rising rates of BPD have been reported.106 Improved treatments and preventive therapies are needed for this growing patient population Systematic reviews support strategies to minimize invasive ventilation and selective use of early surfactant during the initial presentation of RDS to decrease future risk of BPD.19,134 When invasive mechanical ventilation is necessary, a volume-targeted mode may be superior for BPD prevention compared with pressure-limited ventilation.135 Caffeine therapy for apnea of prematurity has been shown to be among the most effective preventive pharmacologic therapies for BPD, with encouraging longer-term neurodevelopmental follow-up.57,58 Vitamin A supplementation has been shown to modestly decrease rates of BPD but requires weekly intramuscular injection.136 Neonatal macrolide therapy for confirmed ureaplasma infection and/or colonization has also been shown to decrease the incidence of BPD.137 Postnatal glucocorticoids have also been investigated as an approach to reduce inflammation and fibrotic injury in the developing lung Unfortunately, early systemic steroid exposures in extremely premature infants have been associated with poor neurodevelopmental outcomes, including increased risk for cerebral palsy, and are not routinely recommended.138 Additionally, iatrogenic adrenal insufficiency, hypertension, hyperglycemia, and immunosuppression are potential side effects of sustained steroid courses Low-dose, limited-duration dexamethasone has been effective in weaning infants at high risk for BPD off mechanical 584 S E C T I O N V Pediatric Critical Care: Pulmonary ventilation.139 Steroid therapy with hydrocortisone has also been investigated both to aid in weaning of mechanical ventilation and early BPD prevention.140,141 Early inhaled and intratracheal instilled steroids likely confer BPD protection but, pending additional investigation and follow-up data, should be used only in clinical trials.142,143 Because the diagnosis of BPD is itself positively associated with neurodevelopmental impairment, risk assessment tools for selective postnatal steroid use in high-risk neonates may be informative in joint decision-making.144 Treatments for infants and children with established BPD vary depending on clinical indication, with few randomized controlled trials to inform the clinician Seasonal respiratory syncytial virus and influenza prophylaxis is recommended but is not uniformly protective Minimizing exposures to environmental hazards (such as tobacco smoke, kerosene burners, and the like) should also be emphasized While many children with BPD may display reactive airways145 (and are often prescribed asthma medications),146 limited evidence exists for the longerterm efficacy of inhaled bronchodilators and corticosteroids or their impact on overall respiratory health.147 Avoidance of extremely premature birth would be the most effective preventive strategy for BPD Until that is possible, much can still be learned about the optimal prevention and treatment of infants with BPD Promising new strategies—including stem cell therapy,148 reducing inflammation and nosocomial infection,112,149 adducts of nitric oxide,150,151 improved recognition and treatment of pulmonary hypertension complications,121 and coordinated interdisciplinary follow-up care152—may provide added benefits Given the multiple factors and broad spectrum of BPD pathophysiology, combinations of strategies in the prevention and management based on neonatal risk factors and disease state may prove to be the most effective approach Neonatal Chronic Lung Disease: Primary Ciliary Dyskinesia Primary ciliary dyskinesia (PCD) is a rare genetic lung disease of dysfunctional ciliary motility that results in heterogeneous otosino-pulmonary disease and laterality defects Greater than 80% of PCD patients have a history of neonatal respiratory distress without a clear explanation such as premature birth.153,154 Newborns with PCD often appear asymptomatic at birth, then between 12 to 24 hours of age begin to develop increased work of breathing, tachypnea, and hypoxemia requiring supplemental oxygen and/or positive pressure ventilation support.155 Newborns with PCD are most commonly diagnosed with neonatal pneumonia or transient tachypnea of the newborn, requiring hospitalization for more than week on average.153,154 In the setting of organ laterality anomalies, PCD should be considered in the neonatal differential diagnosis.155 Year-round daily cough and daily nasal congestion may also present during the first month of age.154 In patients with high clinical suspicion for PCD (2 of findings: unexplained neonatal respiratory distress, organ laterality defect, year-round cough, or year-round nasal congestion), definitive diagnosis may be challenging in patients less than years of age when nasal nitric oxide diagnostic testing can be performed Genetic analysis of known PCD gene variants can be diagnostic during infancy if biallelic PCD-associated genes are identified In instances of single pathogenic variants or variants of unknown significance, it is recommended to pursue pediatric diagnosis by electron microscopy of the ciliary ultrastructure.156 As such, initial PCD evaluation, diagnosis, and counseling should preferably be performed at a PCD Foundation–accredited center.157 Unfortunately, therapeutic studies specific to PCD are lacking Supportive management highlighting airway clearance, antimicrobial treatment of acute exacerbations, and scheduled vaccinations is recommended, with additional case-by-case respiratory therapies as indicated.155 Acknowledgment The authors thank Drs Devaraj Sambalingam and Lewis P Rubin, who contributed to this chapter in the previous edition Key References Abman SH, Ivy DD, Archer SL, et al Executive summary of the American Heart Association and American Thoracic Society Joint Guidelines for pediatric pulmonary hypertension Am J Respir Crit Care Med 2016;194(7):898-906 Berger TM, Allred EN, Van Marter LJ Antecedents of clinically significant pulmonary hemorrhage among newborn infants J Perinatol 2000;20:295-300 Brown MJ, Olver RE, Ramsden CA, et al Effects of adrenaline and of spontaneous labour on the secretion and absorption of lung liquid in the fetal lamb J Physiol 1983;344:137-152 Finer NN, Higgins R, Kattwinkel J, et al Summary proceedings from the apnea-of-prematurity group Pediatrics 2006;117:S47-S51 Garenne M, 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Swaminathan S, Quinn J, Stabile MW, et al Long-term pulmonary sequelae of meconium aspiration syndrome J Pediatr 1989;114: 356-361 44 Stryker CC, Dylag A, Martin RJ Apnea and control of breathing In: Jobe AH, Whitsett JA, Abman SH, eds Fetal and Neonatal Lung Development: Clinical Correlates and Technologies for the Future New York: Cambridge University Press; 2016:223-237 ... vasculature and epithelial thinning to form functional gas exchange units Stage 4: Saccular—additional branching and lengthening of the acinar tubules and buds to form thin-walled alveolar saccules... strategies Postnatal factors PREMATURE LUNG Noninvasive positive pressure, selective surfactant Methylxanthines, vitamin A, macrolides BPD LUNG Postnatal steroids, nutrition, diuretics • Fig 51.2 Multiple... growth failure may further complicate the postnatal course Likely due to their increased work of breathing, infants with BPD have increased caloric requirements (140–150 kcal/kg per day).119 Given