CHAPTER 24 1. Describe the anatomic and biochemical events associated with lung development. 2. Discuss the physiology of respiration. 3. Describe common respiratory disorders seen in the newborn infant. 4. Discuss common findings in respiratory distress syndrome, meconium aspiration syndrome, pneumonia, pulmonary hypertension, and bronchopulmonary dysplasia. 5. Describe nonpulmonary causes of respiratory distress. 6. Identify treatment strategies for common respiratory problems. 7. Formulate a plan of care for infants with respiratory disorders. The most common life-threatening diseases in newborns are respiratory in origin. This is evidenced by the number of infants admitted to the neonatal intensive care unit (NICU) in respiratory distress. Respiratory distress syndrome (RDS), retained lung fluid syndromes, aspiration syndromes, air leaks, and congenital pneumonia account for approximately 90% of all respiratory distress in newborns. Pulmonary disease, however, is not the cause of all respiratory distress in newborn infants. Congenital malformations, metabolic abnormalities, central nervous system (CNS) disorders, and congenital heart disease may also present with respiratory distress. This chapter discusses common respiratory problems of the newborn infant, along with pathophysiology, clinical presentation, differential diagnosis, and management. A. Anatomic events. Five stages of lung development have been identified and are described as follows (Diehl-Jones, 2012): 2. Pseudoglandular period (weeks 6 to 16). All conducting airways are formed. Cartilage appears; main bronchi are formed; demarcation of major lobes occurs; formation of new bronchi is complete; capillary bed is formed with connecting bronchial blood supply; no connection made with terminal air sacs. The lung at this time undergoes 14 more generations of branching and the formation of the terminal bronchioles. The lung resembles an exocrine organ because of surrounding loose mesenchymal tissues, hence the name pseudoglandular. 3. Canalicular period (weeks 16 to 26). Formation of gas-exchanging acinar units (i.e., respiratory units). The appearance of glycogen-rich cuboidal cells and inclusions for surface-active material storage are seen; capillaries invade terminal airway walls; type II alveolar epithelial cells appear. Airway changes from glandular to tubular and increases in length and diameter. Vascular system proliferates and the capillaries are now closer to the epithelium-conducting airways. Respiratory bronchioles that will participate in gas exchange can be differentiated. 4. Terminal sac period (weeks 26 to birth). Around week 26 alveolar sacs are formed; air–blood surface area is limited for gas exchange; and type II cells are unable to release surfactant in sufficient quantity to maintain air breathing. Capillary loops increase; type II cells cluster at alveolar ducts, become numerous and mature; more budding occurs from alveolar ducts; and lung size increases rapidly because there is an exponential increase in surface area for gas exchange. 5. Alveolar period (week 32 to 8 to 10 years). This phase is characterized by continued alveolar proliferation and development. B. Biochemical events. 2. Surfactant is a mixture of at least six phospholipids and four apoproteins. a. Dipalmitoylphosphatidylcholine (DPPC) is the major surface-active lipid component of surfactant. DPPC reduces the surface tension at the air–water interface in the alveolus almost to zero (Diehl-Jones, 2012). b. Surfactant includes cholesterol, proteins, complex carbohydrates, and glycolipids. c. Phospholipids are responsible for the surface-active properties of surfactant. Surfactant proteins have recently been found to have important properties. d. There are two groups of surfactant proteins: the hydrophilic surfactant proteins A and D (SP-A and SP-D) and the hydrophobic surfactant proteins B and C (SP-B and SP-C). SP-B and SP-C are known to enhance the surface tension–lowering properties of surfactant and facilitate its absorption and spread. (2) SP-B is important in the formation of tubular myelin, enhances the uptake of phospholipids by the type II cell, and is also important in the recycling of surfactant. (3) SP-C may have a role in surfactant dispersal and recycling, enhancing the rate of absorption and spreading of surfactant. (4) SP-D may also have a role in host defense mechanisms and is upregulated during periods of acute lung inflammation (Gaunsbaek et al., 2013). e. Surfactant reduces surface-tension forces in the alveoli that are capable of producing collapse at expiration (Diehl-Jones, 2012). (1) Surfactant is produced in the type II pneumocyte beginning at 25 to 30 weeks of gestation and continuing to term (Diehl-Jones, 2012). Type II pneumocytes synthesize, store, secrete, and recycle surfactant (Blackburn, 2013). (2) When the lungs are inflated, receptors in type II cells mobilize intracellular calcium, which causes the release of the contents of lamellar bodies into the air space. After secretion, surfactant may be taken back into type II cells with a turnover time of 10 hours. 3. The changing pattern of phospholipids in amniotic fluid can be used to assess surfactant production and maturation of pathways. a. Material from the fetal lung contributes to amniotic fluid. b. Concentrations of various phospholipids can be measured and will assist in determining lung maturity. 4. Sphingomyelin concentration remains stable, with a small peak at 28 to 30 weeks. 5. Lecithin and phosphatidylinositol concentrations remain low until 26 to 30 weeks, when an increase begins. A peak occurs at 36 weeks. 6. Phosphatidylglycerol (PG) appears at 30 weeks, peaks at 35 to 36 weeks, and increases as the phosphatidylinositol level falls. a. When PG is present, the risk that RDS will develop in the infant is less than 1%. b. PG is measured as absent or present. c. Blood and meconium do not affect test results. 7. The lecithin/sphingomyelin (L/S) ratio has been used to assess fetal lung maturity. a. An L/S ratio greater than 2:1 is considered to indicate fetal lung maturity. b. An infant of a diabetic mother may develop RDS even with a mature L/S ratio (presence of PG ensures lung maturity). c. Chronic fetal stress (e.g., maternal hypertension, retroplacental bleeding, maternal drug use, smoking) will tend to accelerate surfactant production, resulting in a mature L/S ratio in premature infants. 8. Fetal lung maturity. a. Measures ratio of surfactant to albumin. b. Sample should be free of blood and meconium. c. Less than 50 = immaturity; 50 to 70 = borderline maturity; greater than 70 = mature lungs. C. Role of antenatal steroids (American College of Obstetrics and Gynecology [ACOG], 2011). 1. Antenatal corticosteroids and glucocorticoids (e.g., betamethasone or dexamethasone) affect lung maturation and present a strategy for preventing RDS. Betamethasone appears to significantly decrease neonatal death and morbidity (Mwansa-Kambafwile et al., 2010; Roberts and Dalziel, 2008). Steroids accelerate the normal pattern of lung growth by increasing the rate of glycogen depletion and glycerophospholipid biosynthesis. This leads to thinning of the intra-alveolar septa and increases the size of the alveoli. The number of surfactant-producing type II pneumocytes increases, as does the number of lamellar bodies inside the cells. This leads to increased synthesis of surfactant phospholipids. Steroids may also increase the amount of fibroblast pneumocyte factor, which increases surfactant production (Blackburn, 2013). a. Treatment with steroids is recommended for: (1) Maternal risk of preterm delivery between 24 and 34 weeks of gestation. (2) Treatment with corticosteroids less than 24 hours prior to delivery is still associated with a decrease in mortality, RDS, and intraventricular hemorrhage (IVH). It should be given unless delivery is imminent. b. Administration of corticosteroids in premature rupture of the membranes is not associated with a higher risk of chorioamnionitis. c. Two doses of betamethasone 12 mg should be given intramuscularly (IM) 24 hours apart, or four doses of dexamethasone 6 mg should be given IM every 12 hours in patients at risk for preterm delivery between 24 and 34 weeks of gestation. Repeated courses of glucocorticoids should not be routinely used; however, a single rescue course of steroids may be considered when birth is expected within 1 week if the previous treatment was more than 2 weeks prior and the gestational age of the fetus is less than 33 weeks. 2. Infants exposed to chronic stress in utero are usually small for gestational age and have more mature lungs (they also have small thymuses and large adrenal glands, suggesting high glucocorticoid levels in utero). Refer to Chapters 4 and 26. 2. Increasing respiratory difficulty in the first 3 to 6 hours, leading to hypoxia and hypoventilation. 3. Progressive atelectasis. B. Incidence. 1. Approximately 40,000 infants per year affected in the United States (Orlando, 2012). 2. The incidence of RDS is inversely related to gestational age, affecting 90% to 98% of all premature infants born between 22 and 27 weeks of gestation (Stoll et al., 2010). C. Etiology. 2. Pulmonary hypoperfusion. 3. Anatomic immaturity. 4. Precipitating factors associated with incidence and/or severity of RDS (Hamvas, 2011). a. Prematurity and low birth weight. b. Cesarean delivery without labor. c. Maternal diabetes, especially if infant was born at less than 38 weeks of gestation. d. Second twin (Gardner et al., 2011b). (1) May be due to greater risk of asphyxia. (2) First twin usually smaller, suggesting chronic stress leading to early lung maturation. e. Perinatal hypoxia–ischemia. f. Male/female ratio of 2:1. D. Pathophysiology. 1. Production of surfactant is inadequate, occurring when the utilization of surfactant exceeds the rate of production. This leads to diffuse alveolar atelectasis, pulmonary edema, and cell injury (Jackson, 2012). Progressive worsening of these three factors will contribute to a loss of functional residual capacity, alteration in ventilation–perfusion ratio, and uneven distribution of ventilation (Hamvas, 2011). 2. Serum proteins, which inhibit surfactant function, leak into the alveoli. The increased water content, immature mechanisms for clearance of lung liquid, lack of alveolar–capillary apposition, and decreased surface area for gas exchange, typical of the immature lung, also contribute to the disease (Jobe and Ikegami, 2011). 3. Histologic findings are the presence of hyaline membranes and an eosinophilic material derived from injury to epithelial cells. The alveolar spaces are generally collapsed, with pulmonary edema, hemorrhage, and hemorrhagic edema noted (Hamvas, 2011). E. Clinical presentation. 1. Almost exclusively in premature infants. a. May appear to be a normally grown, healthy premature infant with good Apgar scores at birth. b. Distress begins at or soon after birth. 2. Increasing respiratory difficulty related to progressive atelectasis. Symptoms are progressive. a. Tachypnea (> 60 breaths per minute) is usually the first sign; color may be initially maintained. b. Audible expiratory grunt. (1) Heard during first few hours. (2) Caused by forcing of air past a partially closed glottis. (3) Used to maintain positive end-expiratory pressure (PEEP) at the alveolar level in an attempt to prevent alveolar collapse. (4) More pronounced with severe disease. c. The chest wall in an infant is very compliant. When an infant breathes spontaneously, pleural pressure decreases during inspiration. When there is parenchymal disease, the chest wall produces greater negative pressure and the more compliant chest wall caves inward with a moderate decrease in pleural pressure, which results in retractions. Retractions are seen at the sternum and subcostal and intercostal spaces of the infant’s chest and reflect a decrease in lung volume (Gardner et al., 2011b). d. Nasal flaring. e. Cyanosis due to increasing hypoxemia. 3. Oxygen requirements increase to maintain arterial PO2 at 50 to 70 mm Hg because of decreased lung compliance secondary to decreased surfactant. Additional physical effort is needed to keep terminal airways open, resulting in increased work of breathing. 4. Paradoxical seesaw respirations may be seen. 5. If signs and symptoms are unattended, infant becomes obtunded and flaccid. a. Pallor may obscure severe central cyanosis. b. Poor capillary filling time (> 3 to 4 seconds). c. Progressive edema, usually seen in the face, palms, and soles. 6. Oliguria is common in the first 48 hours. 7. Breath sounds diminish and lung auscultation is usually described as “poor air entry” despite vigorous effort on the infant’s part. 8. Crackles become audible as the disease progresses. 9. Cardiac murmurs are generally not heard until after 24 hours of age. 10. Tachycardia (heart rate > 160 beats per minute [bpm]) is common and even more prevalent if acidosis and hypoxemia are present. F. Diagnosis. 1. Signs and symptoms as previously described. 2. Hypoxemia (defined as arterial PO2 level < 50 mm Hg in room air) as a result of ventilation–perfusion mismatch and right-to-left intrapulmonary shunting, responding to supplemental inspired oxygen; respiratory failure secondary to alveolar hypoventilation (PCO2 > 50; pH ≤ 7.25). 3. Chest x-ray (CXR) reveals low lung volumes, hazy lung fields, and a fine reticulogranular pattern of density with air bronchograms. Occasionally the disease may appear worse in one lung than the other (Hamvas, 2011). 4. Diagnostic studies. b. Arterial blood gas (ABG) measurements. c. Blood cultures, complete blood cell count if risk factors are present. Pneumonia caused by group B streptococcus (GBS) has similar radiographic features; therefore, infection must be considered. d. Blood glucose level. Prematurity and increased work of breathing results in increased glucose consumption. G. Differential diagnosis. 2. Transient tachypnea of the newborn (TTN) can present with the same signs and symptoms, but these infants usually require ≤ 40% FiO2, improve more quickly, and have larger lung volumes on CXR. 3. Pulmonary edema. A primary cardiac disorder with pulmonary edema (such as a patent ductus arteriosus [PDA]) can mimic RDS. H. Complications. b. Pulmonary edema. c. Bronchopulmonary dysplasia (BPD). 2. Cardiovascular. b. Systemic hypotension. 3. Renal. (1) Most likely to follow hypoxia, hypotension, or shock (“prerenal” renal failure). b. Immature renal function with decreased glomerular filtration in very low birth weight infants. c. Natural diuresis will occur at approximately 48 to 72 hours of age, as infant’s condition improves. 4. Metabolic. a. Acidosis. Atelectasis with increased work of breathing will lead to hypoxemia and acidemia, resulting in vasoconstriction of the pulmonary vasculature (Orlando, 2012). This then limits alveolar capillary blood flow, which further impedes the production of surfactant and compounds the problem. b. Hyponatremia or hypernatremia. c. Hypocalcemia. d. Hypoglycemia. 5. Hematologic. 6. Neurologic. a. Seizures: may result from hypoglycemia or an IVH. b. Hypoxia, positive pressure ventilation, rapid fluid infusions, rapid pH shifts, and acidosis are all factors causing changes in cerebral blood flow that may precipitate an IVH (Verklan and Lopez, 2011). 7. Other. a. Secondary nosocomial infections. b. Retinopathy of prematurity (ROP). c. Dislodged endotracheal tubes. d. Thrombus formation. Complication of umbilical catheters and peripheral central catheters needed to monitor respiratory status and provide adequate nutrition. I. Management. RDS is a disease that is self-limited and transient. Adequate surfactant can be produced by the premature infant within 48 to 72 hours. 1. Goal of treatment is supportive until disease resolves and to prevent further lung injury (Orlando, 2012). 2. Surfactant replacement therapy. a. Benefits include the following (Engle and Committee on Fetus and Newborn, 2008): (1) Reduced morbidity and mortality rates. (2) Improved compliance and decreased resistance in surfactant-poor acini, thereby reducing the pressure needed to inflate the lungs and decreasing work of breathing. (3) Improved ventilation in low-volume lung units, which increases the PaO2, decreases the right-to-left intrapulmonary shunt, and improves overall oxygenation of the infant. b. Surfactants approved by U.S. Food and Drug Administration (FDA) for treatment of RDS: (2) A synthetic form of surfactant (Surfaxin) was approved in 2012. c. Three treatment approaches are related to timing. (1) Prophylaxis. Treatment within 15 minutes of birth: infants born at less than 27 to 30 weeks of gestation, especially if the mother did not receive antenatal steroids; dose given via endotracheal tube after initial resuscitation. Additional doses may be given if necessary. Prophylactic use of surfactant has been shown to decrease the incidence and severity of RDS and to reduce the risk of air leak, BPD, and death (Bahadue and Soll, 2012; Engle and Committee on Fetus and Newborn, 2008). Because of the risks associated with intubation, controversy exists as to which infants should be selected for prophylactic surfactant (Jackson, 2012). (2) Early rescue. Treatment of infants within 1 to 2 hours of life with signs of RDS; multiple doses can be given. The goal of intervention is to avoid progressive alveolar atelectasis leading to respiratory failure requiring intermittent positive pressure ventilation (IPPV) (Jackson, 2012). (3) Late rescue: treatment at 4 to 6 hours of age for infants requiring mechanical ventilation and more than 40% FiO2. Early or prophylactic therapy has been shown to confer more benefit than late rescue treatment (Bahadue and Soll, 2012); however, by delaying intubation and surfactant administration, some infants who otherwise may have been intubated and treated may be successfully managed with noninvasive treatment methods such as nasal continuous positive airway pressure (CPAP) (Rojas-Reyes et al., 2012). (4) Combining surfactant administration and CPAP: In an effort to avoid intubation and mechanical ventilation, many centers are now using an approach that combines intubation and surfactant administration with immediate extubation to nasal CPAP. This approach, referred to as INSURE, has been shown to reduce the need for subsequent mechanical ventilation in low birth weight infants (Kandraju et al., 2013; Pfister and Soll, 2012; Sandri et al., 2010). (5) Administering surfactant without intubation: In an effort to provide the benefit of early surfactant administration while avoiding the hazards of intubation, some centers are studying the administration of surfactant through small catheters inserted into the trachea (Dargaville et al., 2013) or via a laryngeal mask (Attridge et al., 2013). The development of less invasive methods of surfactant delivery is likely to result in increased utilization and potential benefit to the very low birth weight infant. (6) Beractant (Survanta): Dose is 4 mL/kg through the endotracheal tube above the carina. Four doses can be given during the first 48 hours of life (Gardner et al., 2011b). (7) Poractant alfa (Curosurf): Initial dose is 2.5 mL/kg given in two aliquots via the endotracheal tube. Two subsequent doses of 1.25 mL/kg can be administered at 12-hour intervals if needed (Gardner et al., 2011b). (8) Calfactant (Infrasurf): Given via the endotracheal tube, dose is 3 mL/kg divided in two aliquots, every 12 hours for a total of three doses if needed (Gardner et al., 2011b). (9) Lucinactant (Surfaxin): Dose is 5.8 mL/kg given via the endotracheal tube. Up to four doses can be given in the first 48 hours if needed (Gardner et al, 2011b). 3. Provide warm, humidified oxygen to maintain normal PaO2. 4. Provide CPAP via nasal prongs or endotracheal tube if indicated. 5. Use assisted ventilation for profound hypoxemia (PaO2 < 50 mm Hg) and/or hypercapnia (PaCO2 > 60 mm Hg). 6. Monitor oxygenation by pulse oximetry and/or transcutaneous monitoring. 7. Monitor pulmonary status with CXR examination, as clinically indicated. 8. Other measures. b. Provide adequate fluid and electrolyte intake. Monitor intake and output, blood urea nitrogen, and serum creatinine. c. Monitor arterial/capillary blood gases, electrolytes, calcium, bilirubin, and glucose. d. Monitor blood pressure for hypotension. Give pharmacotherapeutic agents (e.g., dopamine, dobutamine, or hydrocortisone) as indicated. e. Maintain hematocrit. f. Administer antibiotics for associated pneumonia/rule out sepsis. g. Optimize nutrition with early introduction of total parenteral nutrition with protein and initiation of minimal enteral feeds as soon as the infant is medically stable. J. Prevention of RDS. 1. Maternal glucocorticoid administration prenatally. 2. Use of L/S ratio, fetal lung maturity, and PG determination for timing labor induction or elective cesarean delivery. 3. Perinatal management to avoid situations leading to pulmonary circulation compromise in the fetus or newborn infant. (2) Oversedation. (3) Maternal hypoxia. (4) Fetal distress without prompt delivery. b. Neonatal. (2) Uncorrected hypoxia or acidosis. (3) Hypothermia, hypoglycemia, and hypovolemia. K. Outcome. 2. Infants who weigh greater than 1500 g who have mild to moderate RDS have the same developmental outcome as infants of the same gestational age without RDS. 3. Factors associated with poorer neurodevelopmental outcome include chronic lung disease, neonatal infection, severe ROP, periventricular leukomalacia (Horbar et al., 2012), grade 3 or 4 IVH (Payne et al., 2013), poor postnatal growth (Belfort et al., 2011), younger gestational age, and male sex (Moore et al., 2012). A. Definition. Infection of the fetal or newborn lung; may be intrauterine or neonatal. a. Passage of infecting agent by infection of fetal membranes. b. Transplacental transmission. c. Aspiration of meconium or infected amniotic fluid during delivery. 2. Neonatal infection. a. Acquired during nursery stay. b. Pathogens are generally different from those acquired in utero. c. Results from passage from other infants, equipment, or caregivers. B. Incidence. 1. Neonatal pneumonia occurs in 1% of term infants and in 10% of preterm infants (Abu-Shaweesh, 2011). The incidence varies by institution and according to causative agent. 2. The incidence of ventilator-acquired pneumonia (VAP) is more difficult to determine because of the difficulty in applying diagnostic criteria to newborn infants; however, estimates place the rates of VAP at 0.7 to 2.2 per 1000 ventilator days (Edwards et al., 2009). C. Etiology. 1. Risk of infection greatest in premature infants because of immature immune system and lack of protective maternal antibodies. Pneumonia can occur by several routes: transplacental, amniotic fluid, at delivery, and nosocomially (Abu-Shaweesh, 2011). 2. Immature ciliary system in the tracheobronchial tree, leading to suboptimal removal of inflammatory debris, mucus, and pathogens. The number of pulmonary macrophages is insufficient for bacterial clearance (Orlando, 2012). 3. Multiple organisms cause neonatal pneumonia (Box 24-1). D. Pathophysiology. a. Infant may be born critically ill or stillborn to a mother with a history of chorioamnionitis. Evidence of pulmonary inflammation is found in 15% to 38% of stillborn infants at autopsy (Abu-Shaweesh, 2011). Other factors linked to congenital pneumonia include excessive obstetric manipulation, prolonged labor with intact membranes, maternal fever, and maternal urinary tract infection (Orlando, 2012). b. Prolonged rupture of membranes (> 18 hours); ascending organisms may infect amniotic fluid. If mother is in active labor, contamination occurs more rapidly. c. Infective organisms may cross the placenta and enter the fetal circulation, causing septicemia that may present as pneumonia. d. Infants usually show signs of generalized illness from birth, but signs of illness may be delayed hours to days if the infective fluid is aspirated during delivery. 2. Neonatal pneumonia. a. Infection occurs days to weeks after birth. b. Pathogenic organism is acquired from hospital personnel, parents, or other infected infants. c. Both bacterial and viral pathogens are associated with neonatal pneumonia. The most common bacterial organisms include GBS, Escherichia coli, Klebsiella, Pseudomonas, Proteus, Staphylococcus epidermidis, group A streptococci, Listeria, Enterobacter, Staphylococcus aureus, Mycoplasma, and Ureaplasma. Viral infections such as herpes, cytomegalovirus, Toxoplasma gondii, varicella-zoster virus, RSV, enterovirus, adenovirus, and parainfluenza virus are also seen (Abu-Shaweesh, 2011; Orlando, 2012). E. Clinical presentation. 1. Labor greater than 24 hours. a. Prolonged rupture of membranes (> 18 hours). b. Maternal fever/chorioamnionitis. c. Foul-smelling or purulent amniotic fluid. d. Fetal tachycardia. e. Decreased fetal heart rate variability. 2. Signs and symptoms. a. Often indistinguishable from other forms of respiratory distress and sepsis. b. Tachypnea, grunting, retractions, cyanosis, hypoxemia, hypercapnia, and hypoglycemia. c. With severe involvement, shock-like syndrome, usually in the first 24 hours of life, with recurrent apnea followed by cardiovascular collapse, profound hypoxemia, and persistent pulmonary hypertension. These signs represent a poor prognosis. 3. Physical examination. a. Physical signs are variable. b. Diminished breath sounds may be present over one or more areas. c. In addition, localized dullness, harshness, or rales may be audible. d. Radiologic findings can mimic those seen with RDS. In addition, pleural effusions may be seen on CXR with GBS pneumonia. F. Diagnostic evaluation. 1. History of any previously mentioned contributing factors is suggestive. 2. Infant may require resuscitation in the delivery room. 3. CXR findings are variable. a. Unilateral or bilateral alveolar infiltrates. b. Diffuse interstitial pattern. c. Pleural effusions. 4. Blood culture because septicemia may present as pneumonia. 5. A complete blood cell count may show neutropenia/leukopenia or may have an abnormal ratio of immature to total neutrophils. 6. Polymerase chain reaction (PCR) to detect herpes viruses. 7. ABG values should be obtained because metabolic acidosis may be severe. 8. Tracheal aspirate culture should be obtained, especially if the infant has an endotracheal tube in place. 9. Cerebrospinal fluid cultures should be obtained when infant is stable, because meningitis often accompanies pneumonia. G. Differential diagnosis. 2. Sepsis/meningitis. 3. TTN. 4. Meconium aspiration. 5. Lung hypoplasia. 6. Pulmonary hemorrhage. 7. Congenital heart disease. H. Complications. 1. Cardiopulmonary complications similar to those of RDS. 2. Systematic inflammatory response syndrome. 3. Disseminated intravascular coagulopathy (DIC). 4. Persistent pulmonary hypertension. 5. Meningitis. I. Management. 1. Antibiotic therapy (see Chapter 32). 2. Maintain normal temperature. 3. Monitor glucose levels. 4. Monitor blood pressure and treat hypotension. 5. Use oxygen with or without assisted ventilation to maintain normal ABG values. 6. Correct respiratory and metabolic acidosis. 7. Provide adequate fluid and electrolyte intake. 8. Monitor for evidence of DIC. 9. High-frequency ventilation, nitric oxide, and extracorporeal membrane oxygenation (ECMO) have been used for patients who are critically ill with pneumonia, with variable outcomes. 10. Provide support for the family. A. Definition. Delayed clearance of the fetal lung fluid—TTN. B. Incidence 1. TTN occurs at a rate of 5.7 per 1000 live births (Abu-Shaweesh, 2011). C. Clinical presentation. 1. Term and near-term infants. 2. In first few hours, tachypnea results in respiratory rates of 60 to 120 breaths per minute; grunting and retractions may also be present. 3. Hypercapnia and respiratory acidosis. 4. Duration may be 1 to 5 days. D. Etiology. 1. Delay in removal of lung fluid. 2. Excessive amount of lung fluid. E. Pathophysiology. 2. Infants at highest risk for retained fetal lung fluid include the following: b. Cesarean delivery without labor. c. Breech delivery. d. Second twin. e. Maternal asthma. f. Precipitous delivery. g. Delayed cord clamping (results in a transfusion of blood, which may transiently elevate the central venous pressure). h. Macrosomia. i. Male sex. j. Maternal sedation. 3. TTN may originate from reduced lung compliance because of delayed reabsorption of lung fluid at the time of birth and/or the distention of interstitial spaces by fluid, leading to alveolar air trapping and decreased lung compliance (Whitsett et al., 2005). 4. Delayed clearance of lung fluid by pulmonary lymphatic system. The retained fetal lung fluid accumulates in the peribronchiolar lymphatics and bronchovascular spaces and interferes with forces promoting bronchiolar patency, and results in bronchiolar collapse with air trapping or hyperinflation. Hypoxemia results from continued perfusion of poorly ventilated alveoli, and hypercarbia results from mechanical interference with alveolar ventilation. Decreased lung compliance results in tachypnea and increased work of breathing (Abu-Shaweesh, 2011). F. Diagnosis. 2. CXR examination reveals diffuse haziness and streakiness in both lung fields, with clearing at the periphery. Fluid may be present in the interlobar fissures, and mild hyperinflation may be present. 3. Diagnosis is frequently one of exclusion. G. Differential diagnosis. 2. Pneumonia/sepsis. H. Management. 1. Because diagnosis is not conclusive, other disorders should be ruled out. 2. Supportive management. a. CPAP with or without supplemental oxygen. b. Temperature regulation. c. Adequate fluid intake and nutritional support. d. Maintain ABGs within acceptable levels. e. Maintain blood glucose at normal levels. 3. If respiratory rate is greater than 60 breaths per minute, delay feedings to avoid possible aspiration. 4. If history indicates risk of infection, broad-spectrum antibiotics (e.g., ampicillin and gentamicin) should be administered until culture results are negative. I. Outcome. 2. Need for respiratory support and tachypnea decreases steadily over several days. Infant may remain mildly tachypneic beyond the need for CPAP. 3. Some infants with TTN have high pulmonary artery pressures documented by echocardiography. If hypoxemia and tachypnea persist, persistent pulmonary hypertension of the newborn (PPHN) may be present. A. Definition. PPHN is caused by right-to-left shunting through the fetal shunts at the atrial and ductal levels. It is secondary to persistent elevation of pulmonary vascular resistance (PVR) and pulmonary artery pressure (Parker and Kinsella, 2012). Seventy-seven percent of infants are diagnosed in the first 24 hours of life, 93% diagnosed by 48 hours of life, and 97% of the infants by 72 hours of life (Gardner et al., 2011b). Incidence is 1.9 per 1000 live births (Roofthooft et al., 2011). B. Pathophysiology. 2. Over the first 12 to 24 hours of life, PVR normally falls by 50% of its total decline (Delaney and Cornfield, 2012). 3. When PVR remains high, adaptation from fetal to neonatal circulation is impaired. 4. Neonatal pulmonary vessels have greater vasoactive properties than adult pulmonary vessels and respond to hypoxia and acidosis with vasoconstriction. Numerous factors increase and decrease PVR. 5. Development of increased vascular smooth muscle contributes to vasospasm. Development of pulmonary artery musculature occurs late in gestation, making PPHN generally a condition of the term and post-term infant. 6. High PVR and pulmonary hypertension impede pulmonary blood flow, which promotes hypoxemia, acidemia, and lactic acidosis. 7. Newborns with persistent elevation of PVR share several characteristics, including abnormal pulmonary vasoreactivity, diminished response to vasodilating stimuli, and increased circulating levels of endothelin, a vasoconstrictor (Delaney and Cornfield, 2012). 8. Studies have described low plasma arginine and nitric oxide metabolites in infants with PPHN, suggesting that a genetic link of the urea cycle may contribute to this process of PPHN (Pearson et al., 2001). C. Etiology. 1. Maladaptation. The pulmonary vascular bed is structurally normal, but PVR remains high. Maladaptation generally results from active vasoconstriction, which may be transient or persistent (Delaney and Cornfield, 2012). b. Pulmonary parenchymal disease (RDS, meconium aspiration, pneumonia, other aspiration syndromes) can cause pulmonary vasospasm and may be associated with vascular remodeling. c. Bacterial sepsis. The underlying mechanism may be endotoxin-mediated myocardial depression or pulmonary vasospasm associated with high levels of thromboxanes and leukotrienes. d. Prenatal pulmonary hypertension. (1) Fetal systemic hypertension. (2) Premature closure of ductus arteriosus, associated with maternal use of aspirin, prostaglandin inhibitors (nonsteroidal antiinflammatory drugs [NSAIDs]), phenytoin (Dilantin), lithium, or indomethacin. However, some studies have shown no increase in PPHN rates in infants exposed to NSAIDs in utero (Van Marter et al., 2013). (3) Maternal selective serotonin reuptake inhibitors use in late pregnancy is associated with a two-fold increase in the risk of PPHN in the newborn (Kieler et al., 2012). (4) Maternal conditions including diabetes, asthma, preeclampsia, and smoking. e. Any condition preventing normal circulatory transition at delivery (CNS depression, delayed resuscitation, hypothermia). f. Hypothermia and hypoglycemia contributing to acidosis, which will potentiate pulmonary vasoconstriction. g. Hyperviscosity/polycythemia. This may lead to a functional obstruction of the pulmonary vascular bed. 2. Maldevelopment: abnormal pulmonary vessels. Musculature is hypertrophied and extends into normally nonmuscularized arteries. The excessive muscularization affects lumen size, which increases vascular resistance. Causes of maldevelopment include the following: b. Fetal ductal closure: forces cardiac output from the right ventricle through the lungs, resulting in maldevelopment. c. Congenital heart disease: abnormal pulmonary vessels resulting from various defects. 3. Underdevelopment: decreased number of pulmonary vessels. Blood is shunted because there are too few vessels for blood to flow through the lungs. There is a decreased cross-sectional area available for gas exchange. Severity depends on the timing of the interruption of lung development in utero: reduced numbers of bronchial generations if early (< 16 weeks) and decreased number of alveoli if later in gestation. Contributing conditions include the following: a. Pulmonary hypoplasia (i.e., Potter sequence). b. Space-occupying lesions or lung masses (e.g., diaphragmatic hernia, cystic adenomatoid malformation) that prevent normal development of lung tissue and the capillary bed. c. Congenital heart disease. Pulmonary atresia or tricuspid atresia may lead to decreased blood flow and vascular underdevelopment. D. Clinical presentation. 1. Near-term, term, or post-term infants. 2. History of hypoxia or asphyxia at birth. b. Infant usually slow to breathe or difficult to ventilate. c. Meconium-stained fluid, nuchal cord, abruptio placentae or any acute blood loss, and maternal sedation. 3. Respiratory abnormalities. a. Symptoms seen before 12 hours of age. b. Tachypnea. c. Retractions if airway is obstructed (e.g., because of aspiration). d. Cyanosis out of proportion to degree of distress; cyanosis of sudden onset that often is intractable. e. Low PaO2 despite high oxygen concentration administration because of right-to-left shunting. Differences are seen between preductal and postductal oxygenation. f. CXR may be normal unless aspiration or pneumonia present (will see infiltrates in these cases). 4. Cardiovascular abnormalities. a. Blood pressure is usually lower than normal. b. Electrocardiogram will show a right axis deviation. c. Systolic murmur is frequently heard, usually from a PDA, foramen ovale, or tricuspid insufficiency. Single loud second heart sound (S2), resulting from high pulmonary pressures, may be heard. d. Echocardiogram shows dilated right side of the heart and evidence of pulmonary hypertension and shunting across the foramen ovale. e. Congestive heart failure has been reported occasionally. 5. Metabolic abnormalities. b. Hypocalcemia. c. Metabolic acidosis. d. Decreased urine output or coagulopathy caused by kidney and liver damage from asphyxia may occur. E. Diagnosis. 1. PPHN will be suspected on the basis of history and clinical course. 2. Pre- and postductal arterial blood samples or oxygen saturation monitoring. Because of the right-to-left shunting at the level of the ductus arteriosus, there will be a preductal and a postductal PaO2 difference. Difference in PaO2 of 15 mm Hg or greater documents ductal shunting (Orlando, 2012). 3. Hyperoxia test. A right-to-left shunt is demonstrated if PO2 does not increase in 100% oxygen. Cause may be either PPHN or congenital heart disease. 4. An echocardiogram will rule out structural heart disease, evaluate myocardial function, measure pulmonary artery pressures, and diagnose right-to-left shunting at the level of the PDA or foramen ovale. 5. CXR may or may not be helpful, but should be taken to rule out other lung pathology. 6. Electrolytes, calcium, serum lactate, and glucose levels and complete blood cell count should be obtained. 7. An ABG measurement is done to determine degree of acidosis and hypoxemia. F. Differential diagnosis. 2. Pulmonary disease. a. Severe disease may mimic PPHN. b. Disease may coexist with PPHN. G. Complications. a. Air leaks. Related to high mean airway pressures used in ventilator management. b. BPD. 2. Cardiovascular. b. Congestive heart failure. 3. Renal. a. Decreased urine output related to asphyxia and hypotension. b. Acute tubular necrosis caused by asphyxia. c. Hematuria, proteinuria. 4. Metabolic. a. Hypoglycemia, hypocalcemia. b. Metabolic acidosis. 5. Hematologic. b. DIC: depends on precipitating cause of PPHN. c. Hemorrhage (e.g., gastrointestinal, pulmonary). 6. Neurologic. b. Neurodevelopmental delay. 7. Iatrogenic. a. Thrombus formation or complications of invasive monitoring equipment. b. Dislodged endotracheal tube. 8. Other. a. Edema due to “third spacing.” b. Side effects of pharmacologic agents used for treatment. H. Management. 2. Management will depend on the cause of PPHN. 3. Supportive care. b. Temperature stabilization. Avoid exposure to cold drafts, which can trigger pulmonary vasoconstriction (diving reflex). c. Adequate intravenous (IV) fluid infusion. d. Monitor electrolytes, glucose, calcium, complete blood cell count, ABGs. e. Correction of metabolic abnormalities. f. Blood cultures and antibiotics. 4. Specialized monitoring. (1) Arterial: blood gas access, arterial pressure monitoring. (2) Venous: infusion of vasopressors. b. Right radial arterial line: monitor preductal blood gases. c. Pulse oximetry. Preductal and postductal applications can be helpful. 5. Oxygen: most potent pulmonary vasodilator. 6. Ventilation. a. Conventional mechanical ventilation. b. High-frequency ventilation (HFV), high-frequency oscillatory ventilation (HFOV), or high-frequency jet ventilation (HFJV). Used when conventional mechanical ventilation fails or when excessive barotrauma is a concern. Meta-analysis has failed to demonstrate a consistent benefit of HFV over conventional ventilation in term infants (Henderson-Smart et al., 2009). (a) Goal is to keep PaO2 at greater than 50 mm Hg. (b) Danger of ROP is minimal because most infants are born at or near term. (2) Adequate ventilation to keep PaCO2 values in normal range. Low normal CO2 levels aid in reducing acidosis and pulmonary artery pressure caused by the vasoconstriction effects of hypercapnia. Previous practices of hyperventilation to induce hypocarbia are less commonly used because of the adverse effects of low CO2 levels (Orlando, 2012). c. Inhaled nitric oxide (iNO) reduces death or the need for ECMO in infants with PPHN. Oxygenation improves in about 50% of infants receiving iNO. A similar benefit of iNO for infants with congenital diaphragmatic hernia has not been demonstrated (Finer and Barrington, 2006). (1) iNO is a selective pulmonary vasodilator. (a) Potent and short acting, with a half-life of 3 to 5 seconds. (b) Combines with hemoglobin and becomes inactivated. (c) Inactivation results in formation of methemoglobin; levels need to be monitored during treatment. (2) A starting doses of 20 parts per million (ppm) in term newborn infants with PPHN is commonly used (Dhillon, 2012). Weaning should be aimed at reducing the dose to less than 10 ppm by 4 hours of age (Kinsella and Abman, 2011). (3) iNO withdrawal (weaning) needs to be systematic; in some infants abrupt discontinuation may result in rebound increased PVR (Kinsella and Abman, 2011). (4) Infants with severe parenchymal lung disease/underinflation and PPHN respond better to iNO when it is combined with HFOV. d. Surfactant replacement: especially for etiology based on significant parenchymal disease (Orlando, 2012). e. ECMO may be used when conventional therapies are unsuccessful. 7. Minimal stimulation and handling. b. The pulmonary arteries are very reactive to changes in PaO2; therefore, any action that causes a decrease in PaO2 (e.g., suctioning, blood sampling, vital signs, ventilator changes) will cause further vasoconstriction. c. Suction only as needed to maintain a patent airway. d. Sedatives and analgesics are used for procedures and treatments. e. The bedside nurse must be a strong advocate for these patients and keep noise and environmental stimuli to a minimum. 8. Pharmacologic support (2) Dopamine is the drug of choice. Dopamine is an endogenous catecholamine with a short half-life and must be given by constant infusion. Dosage: 5 to 10 mcg/kg/min of continuous IV infusion. Begin at lowest dose and titrate by monitoring effects (i.e., blood pressure, urine output, capillary refill, perfusion, and heart rate) (Roig et al., 2011). (3) Dobutamine is a synthetic catecholamine with primary β1-adrenergic receptor effects to support blood pressure in patients with shock and hypotension related to myocardial ischemia, pulmonary hypertension, and cardiomyopathy. Dosage: 10 mcg/kg/min by continuous infusion; titrate by monitoring effects (i.e., blood pressure, urine output, capillary refill, perfusion, and heart rate) (Gardner et al., 2011b). (4) Nitroprusside increases cardiac output by decreasing left ventricular preload and afterload, acting on the arterial and venous smooth muscle. Dosage: 0.4 to 5 mcg/kg/min. Closely follow thiocyanate and cyanide levels (Gardner et al., 2011b). (5) Epinephrine is an adrenergic agonist that increases systemic blood pressure, improves cardiac contractility, and elevates heart rate. Dosage: 0.05 to 0.5 mcg/kg/min given as a continuous infusion (Roig et al., 2011). b. Pulmonary vasodilators. (1) iNO (previously described). (2) Sildenafil may be as effective as iNO in improving pulmonary vasodilation (Gardner et al., 2011b). It has been suggested as adjunctive therapy to facilitate weaning of iNO. A Cochrane review of this therapy suggests the need for additional research before widespread adoption (Shah and Ohlsson, 2011). (3) Milrinone improves oxygenation without decreasing systemic blood pressure. Loading dosage: 75 mcg/kg given over 1 hour followed by 0.5 to 0.75 mcg/kg/min (Roig et al., 2011). c. Analgesics and sedatives. (1) Fentanyl citrate. In addition to analgesic effect, fentanyl produces a sedative effect. Dosage: 0.3 to 2 mcg/kg per dose by slow IV push. Repeat as required (usually every 2 to 4 hours). Frequently used as a constant infusion at 0.3 to 5 mcg/kg/hour. Tolerance may develop rapidly, requiring weaning to prevent significant withdrawal symptoms (Gardner et al., 2011a). (2) Morphine sulfate. Dosage: 0.05 to 0.2 mg/kg per dose IV. Repeat as required, usually every 4 hours. For continuous infusion, usual dose is 10 to 15 mcg/kg/hour. Tolerance may develop with prolonged use, requiring slow weaning to prevent significant withdrawal symptoms (Gardner et al., 2011a; Roig et al., 2011). I. Outcome. 1. PPHN survival rate is dependent on the center and the underlying disease process. 2. Residual chronic lung disease is common, although recently low-dose iNO has reduced the need for ECMO and has reduced the occurrence of chronic lung disease in neonates with hypoxemic respiratory failure (Finer and Barrington, 2006). 3. Sensorineural hearing loss is higher among children treated for PPHN. 4. The need for remedial assistance in school is increased in PPHN survivors (Eriksen et al., 2009). A. Definition and etiology of meconium aspiration syndrome (MAS). 1. Meconium is a mixture of epithelial cells and bile salts found in the fetal intestinal tract. 2. With intrauterine stress or asphyxia, peristalsis is stimulated and relaxation of the anal sphincter occurs, releasing meconium into the amniotic fluid. Postmature fetuses pass meconium more readily than those that are less mature. 3. Aspiration may occur whenever meconium passes into the amniotic fluid, but the risk increases when repeated episodes of severe asphyxia lead to gasping respirations in utero. B. Incidence. Meconium-stained amniotic fluid is present in approximately 8% to 29% of all newborns delivered. Of these, 5% develop MAS (Orlando, 2012). C. Pathophysiology. 1. Complete or partial airway obstruction can occur. 2. Atelectasis or ball–valve air trapping leads to hyperinflation. 3. A chemical pneumonitis develops (probably caused by bile salts). Inflammation develops that is mediated by neutrophils and macrophages, resulting in edema in the alveoli that interferes with surfactant production and increases surface tension (Edwards et al., 2013; Mokra and Calkovska, 2013). 4. Meconium decreases the levels of surfactant proteins SP-A and SP-B, and large numbers of phospholipids (Mokra and Calkovska, 2013). 5. The hypoxia associated with meconium aspiration increases PVR. D. Clinical presentation/diagnosis. 2. Asphyxia and the results of chronic hypoxia may predispose these infants to PPHN. 3. Vigorous resuscitation is frequently needed in the delivery room because of central depression. 4. Respiratory distress signs are nonspecific and may include tachypnea, nasal flaring, and retractions. 5. Respiratory distress may range from mild and transient to severe and prolonged. 6. If there has been prolonged placental insufficiency, infants may appear to be wasted, with hanging skinfolds (usually around knees, buttocks, and axillae). 7. Nail beds and skin may be stained a yellow-green. 8. The chest may appear to be hyperinflated or barrel shaped. 9. CXR shows hyperexpanded lucent areas mixed with areas of atelectasis throughout lung fields. 10. Expiration phase of respirations may be prolonged. 11. Coarse crackles are common on auscultation. 12. No specific laboratory data are useful for diagnosis of MAS. 13. ABGs will show the following: a. Respiratory and metabolic acidosis in severe cases. b. Low PaO2 even with 100% oxygen administration. E. Complications. b. Pneumonia. c. PPHN. 2. Metabolic. b. Hypoglycemia. c. Hypocalcemia. 3. Neurologic: will depend on degree of hypoxia, if any. F. Management and prevention. a. If the infant is depressed with no respiratory effort and poor muscle tone, and/or has a heart rate less than 100 bpm, direct suctioning of the trachea soon after delivery is indicated, before respirations are established. Clear the mouth and posterior pharynx with a suction catheter to facilitate visualization of the glottis. Tracheal suctioning with an endotracheal tube is recommended. Using a meconium aspirator, suction as you slowly withdraw the endotracheal tube. This procedure should be repeated, if necessary (American Academy of Pediatrics [AAP], 2011). 2. Respiratory care. a. ABGs to determine degree of respiratory compromise and type of therapy needed. b. Assisted ventilation. (2) May choose HFV. (3) iNO if PPHN develops. c. Surfactant replacement therapy every 6 hours for up to four doses has been shown to reduce the risk of air leaks, lessen the need for ECMO, and improve gas exchange (El Shahed et al., 2007; Gizzi et al., 2010). More recently, lung lavage with surfactant has been shown to improve clinical outcome in MAS. Further research in this area is needed to confirm the optimal approach to lung lavage (Choi et al., 2012). G. Outcome. 2. In more severe cases, neurologic sequelae are common and death may occur despite vigorous, maximal support. 1. In 1967, Northway, Rosan, and Porter originally described the four stages of BPD based on the time that the change occurred (from birth to 30 days of life) and on the type of alveolar and bronchial damage and repair that occurred. 2. A more clinically useful definition now focuses on the need for oxygen or ventilatory support. The subjectivity of x-ray changes or clinical symptoms has been removed from this definition (Groothuis and Makari, 2012). 3. A new proposed definition is an infant less than 32 weeks of gestation who has reached 36 weeks of postmenstrual age, was treated with oxygen for greater than 28 days, and requires oxygen or positive pressure at 36 weeks of postmenstrual age (Table 24-1). This definition also established criteria for mild, moderate, and severe BPD (Jobe and Bancalari, 2001). TABLE 24-1 Definition of Bronchopulmonary Dysplasia: Diagnostic Criteria
Respiratory Distress
LUNG DEVELOPMENT
PHYSIOLOGY OF RESPIRATION
RESPIRATORY DISORDERS
Respiratory Distress Syndrome
Pneumonia
Retained Lung Fluid Syndromes—Transient Tachypnea of the Newborn
Persistent Pulmonary Hypertension of the Newborn
Meconium Aspiration Syndrome
Bronchopulmonary Dysplasia
Gestational Age at Birth
< 32 Weeks
≥ 32 Weeks
Time point of assessment
36 weeks PMA or discharge to home, whichever comes first
> 28 days but < 56 days of postnatal age or discharge to home, whichever comes first
Treatment with oxygen > 21% for at least 28 days plus
Mild BPD
Breathing room air at 36 weeks PMA or discharge, whichever comes first
Breathing room air by 56 days postnatal age or discharge, whichever comes first
Moderate BPD
Need* for < 30% oxygen at 36 weeks PMA or discharge, whichever comes first
Need* for < 30% oxygen at 56 days’ postnatal age or discharge, whichever comes first
Severe BPD
Need* for ≥ 30% oxygen and/or positive pressure (PPV or nCPAP) at 36 weeks PMA or discharge, whichever comes first
Need* for ≥ 30% oxygen and/or positive pressure (PPV or nCPAP) at 56 days’ postnatal age or discharge, whichever comes first 
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