Respiratory Tract Disorders

Keywords

• fetal lung fluid

• functional residual capacity

• positive pressure ventilation

• surfactant

• periodic breathing

The First Breath

Initiation of the first breath is caused by a decline in arterial oxygen tension (Pa o ₂ ) and pH and a rise in arterial carbon dioxide partial tension (Pa co ₂ ) as a result of interruption of the placental circulation, redistribution of cardiac output, decrease in body temperature, and various tactile and sensory inputs. The relative contributions of these stimuli to the onset of respiration are uncertain.

Although spontaneously breathing infants do not need to generate an opening pressure to create airflow, infants requiring positive pressure ventilation (PPV) at birth need an opening pressure of 13-32 cm H ₂ O and are more likely to establish FRC if they generate a spontaneous, negative pressure breath. Expiratory esophageal pressures associated with the 1st few spontaneous breaths in term newborns range from 45-90 cm H ₂ O. This high pressure, caused by expiration against a partially closed glottis, may aid in the establishment of FRC but would be difficult to mimic safely with artificial ventilation. The higher pressures needed to initiate respiration are required to overcome the opposing forces of surface tension (particularly in small airways) and the viscosity of liquid remaining in the airways, as well as to introduce about 50 mL/kg of air into the lungs, 20-30 mL/kg of which remains after the first breath to establish FRC. Surfactant lining the alveoli enhances the aeration of gas-free lungs by reducing surface tension, thereby lowering the pressure required to open alveoli. Air entry into the lungs displaces fluid, decreases hydrostatic pressure in the pulmonary vasculature, and increases pulmonary blood flow. The greater blood flow in turn increases the blood volume of the lung and the effective vascular surface area available for fluid uptake. The remaining fluid is removed by the pulmonary lymphatics, upper airway, mediastinum, and pleural space. Fluid removal may be impaired after cesarean birth or as a result of surfactant deficiency, endothelial cell damage, hypoalbuminemia, high pulmonary venous pressure, or neonatal sedation.

Compared with term infants, preterm infants have a very compliant chest wall and may be at a disadvantage in establishing FRC. Abnormalities in ventilation-perfusion ratio are greater and persist for longer periods in preterm infants and may lead to hypoxemia and hypercarbia as a result of atelectasis, intrapulmonary shunting, hypoventilation, and gas trapping. The smallest immature infants have the most profound disturbances as a consequence of respiratory distress syndrome (RDS) . However, even in healthy term infants, oxygenation is impaired immediately after birth, and oxygen saturation (S o ₂ ) gradually increases and exceeds 90% only at about 5 min. In addition, because of the relatively high pulmonary arterial pressure present in the fetal lung, right-to-left shunting across the ductus arteriosus is common soon after birth. If pulse oximetry is performed soon after birth, the recommendation is to measure preductal S o ₂ in the right upper extremity.

Breathing Patterns in Newborns

During sleep in the 1st few mo after birth, normal full-term infants (and more frequently preterm infants) may have episodes when regular breathing is interrupted by short pauses. This periodic breathing pattern is characterized by brief episodes of respiratory pauses lasting 5-10 sec, followed by a burst of rapid respirations at a rate of 50-60 breaths/min for 10-15 sec. The brief interruptions in respiration are not associated with change in color or heart rate. Periodic breathing is a normal characteristic of neonatal respiration and has no prognostic significance.

Keywords

• apnea

• mixed apnea

• central apnea

• obstructive apnea

• apnea of prematurity

• nasal continuous positive airway pressure

• heated humidified high-flow nasal cannula

• methylxanthines

• caffeine

• gastroesophageal reflux

• home monitoring

• sudden infant death syndrome

Apnea of Prematurity

Apnea of prematurity results from immature respiratory control, most frequently occurs in infants <34 wk of gestational age (GA), and occurs in the absence of identifiable predisposing diseases. The incidence of idiopathic apnea of prematurity varies inversely with GA. Apnea of prematurity is almost universal in infants born at <28 wk GA, and the incidence rapidly decreases from 85% of infants <30 wk GA to 20% of infants <34 wk GA. The onset of apnea of prematurity can be during the initial days to weeks of age but is often delayed if there is RDS or other causes of respiratory distress. In premature infants without respiratory disease, apneic episodes can occur throughout the 1st 7 postnatal days with equal frequency.

Apnea in preterm infants is defined as cessation of breathing for ≥20 sec or for any duration if accompanied by cyanosis and bradycardia (<80-100 beats/min). The incidence of associated bradycardia increases with the length of the preceding apnea and correlates with the severity of hypoxia. Short apnea episodes (10 sec) are rarely associated with bradycardia, whereas longer episodes (>20 sec) have a higher incidence of bradycardia. Bradycardia follows the apnea by 1-2 sec in >95% of cases and is most often sinus, but on occasion it can be nodal. Vagal responses and rarely heart block are causes of bradycardia without apnea. Short, self-resolving oxygen desaturation episodes noted with continuous monitoring are normal in neonates, and treatment is not necessary.

Preterm infants born at <35 wk GA are at risk for apnea of prematurity and therefore should receive cardiorespiratory monitoring. Apnea that occurs in the absence of other clinical signs of illness in the 1st 2 wk in a preterm infant is likely apnea of prematurity, and therefore additional evaluation for other etiologies is often unwarranted. However, the onset of apnea in a previously well preterm neonate after the 2nd wk of life (or, as previously, in a term infant at any time) is a critical event that may be associated with serious underlying pathology. Prompt investigation for medication side effects, metabolic derangements, structural CNS anomalies, intracranial hemorrhage, seizures, or sepsis/meningitis is warranted.

Treatment

Gentle tactile stimulation or provision of flow and/or supplemental oxygen by nasal cannula is often adequate therapy for mild and intermittent episodes. Nasal continuous positive airway pressure (nCPAP, 3-5 cm H ₂ O) and heated humidified high-flow nasal cannula (HHHFNC, 1-4 L/min) are appropriate therapies for mixed or obstructive apnea. The efficacy of both nCPAP and HHHFNC is related to their ability to splint the upper airway to prevent airway obstruction. Both are used widely, but nCPAP may be preferred in extremely preterm infants because of its proven efficacy and safety.

Recurrent or persistent apnea of prematurity is effectively treated with methylxanthines . Methylxanthines increase central respiratory drive by lowering the threshold of response to hypercapnia as well as enhancing contractility of the diaphragm and preventing diaphragmatic fatigue. Caffeine and theophylline are similarly effective methylxanthines, but caffeine is preferred because of its longer half-life and lower potential for side effects (less tachycardia and feeding intolerance). In preterm infants, caffeine reduces the incidence and severity of apnea of prematurity, facilitates successful extubation from mechanical ventilation, reduces the rate of bronchopulmonary dysplasia (BPD) , and improves neurodevelopmental outcomes. Caffeine therapy can be safely administered orally (PO) or intravenously (IV) with an initial loading dose of 20 mg/kg of caffeine citrate followed 24 hr later by once-daily maintenance doses of 5 mg/kg (increased to 10 mg/kg daily as needed for persistent apnea). Because the therapeutic window is wide (therapeutic level: 8-20 µg/mL) and serious side effects associated with caffeine are rare, monitoring of serum drug concentrations are usually unnecessary. Monitoring is primarily through observation of vital signs (tachycardia) and clinical response. Higher doses of caffeine may be more effective without serious adverse events, but additional studies are needed to ensure safety. Retrospective cohort studies suggest that initiation of caffeine in the 1st 3 days of age in extremely preterm infants (<28 wk GA) may improve outcomes. However, it is reasonable to delay caffeine therapy until apnea occurs. Caffeine therapy is usually continued until an infant is free of clinically significant apnea or bradycardia for 5-7 days without positive pressure respiratory support, or at 34 wk postmenstrual age (PMA).

In an infant with significant anemia, transfusion of packed red blood cells (RBCs) increases blood O ₂ -carrying capacity, improves tissue oxygenation, and is associated with a short-term reduction in apnea. However, a long-term benefit in regard to apnea appears unlikely. Gastroesophageal reflux (GER) is common in neonates, but despite being associated with apnea anecdotally, data do not support a causal relationship between GER and apneic events. In preterm infants, medications that inhibit gastric acid production have potentially harmful side effects (increased incidence of sepsis, necrotizing enterocolitis, death) and may actually increase the incidence of apnea and bradycardia. Therefore the routine use of medications that inhibit gastric acid synthesis or promote gastrointestinal motility to reduce the frequency of apnea in preterm infants should be discouraged.

Prognosis

In 92% of infants by 37 wk PMA and in 98% of infants by 40 wk PMA, apnea of prematurity resolves spontaneously. However, infants born well before 28 wk GA may experience apnea and bradycardic events until 44 wk PMA. Beyond 44 wk PMA, extreme events (apnea >30 sec and/or bradycardia <60 beats/min for >10 sec) are very rare. The period that an infant should be observed to ensure resolution of apnea and bradycardia is not defined and among institutions is highly variable. However, many experts would recommend that an infant demonstrate an event-free period of 5-7 days before discharge. Although the nature and severity of events should dictate the length of observation, sufficiently large retrospective cohort studies suggest that a 1-3 day (infants born at ≥30 wk GA), 9-10 day (27-28 wk GA), or 13-14 day (<26 wk GA) event-free period predicts resolution of apnea in up to 95% of infants successfully. Brief, isolated bradycardic episodes associated with oral feeding are common in preterm infants and are generally not considered significant during the event-free period. While not recommended routinely for preterm infants with apnea of prematurity, in rare cases an infant with persistent, prolonged apnea may be discharged with home cardiorespiratory monitoring. In the absence of significant events, home monitoring can be safely discontinued at 44 wk PMA. There is no evidence that home monitoring prevents death.

Despite its high frequency in preterm infants, the harm associated with apnea of prematurity is unknown. However, apnea of prematurity does not appear to alter an infant's prognosis unless it is severe, recurrent, and refractory to therapy. Prompt, effective therapy and careful monitoring are vital to avoid prolonged, severe hypoxia, which may increase the risk of death and neurodevelopmental impairment.

Apnea of Prematurity and Sudden Infant Death Syndrome

Although preterm infants are at higher risk for sudden infant death syndrome (SIDS), apnea of prematurity does not further increase that risk. The peak incidence of SIDS occurs earlier in infants born at 24-28 wk GA (47.1 wk PMA vs 53.5 wk PMA). The epidemiologic evidence that placing babies supine during sleep reduces the rate of SIDS deaths by >50% suggests that positioning, and not prematurity, primarily influences the incidence of SIDS. Supine positioning on a firm sleep surface separate from the parents’ bed, promotion of breastfeeding, and pacifier use during sleep reduce the incidence of SIDS. Avoidance of cigarette smoke exposure and no parental use of alcohol or illicit drugs during pregnancy and after birth are also important in the prevention of SIDS.

Keywords

• respiratory distress syndrome

• hyaline membrane disease

• surfactant

• oxygen toxicity

• tachypnea

• expiratory grunting

• nasal flaring

• retractions

• antenatal corticosteroids

• betamethasone

• nasal continuous positive airway pressure

• heated humidified high-flow nasal cannula

• surfactant replacement therapy

• mechanical ventilation

• bronchopulmonary dysplasia

• respiratory compliance

• volume-targeted ventilation

• pressure-limited ventilation

• high-frequency ventilation

• permissive hypercapnia

• extrapulmonary air leak

Incidence

Respiratory distress syndrome (RDS) occurs primarily in premature infants; its incidence is inversely related to gestational age and birthweight. It occurs in 60–80% of infants <28 wk GA, in 15–30% of those between 32 and 36 wk GA, and rarely in those >37 wk GA. The risk for development of RDS increases with maternal diabetes, multiple births, cesarean delivery, precipitous delivery, asphyxia, cold stress, and a maternal history of previously affected infants. The risk of RDS is reduced in pregnancies with chronic or pregnancy-associated hypertension, maternal heroin use, prolonged rupture of membranes, and antenatal corticosteroid prophylaxis.

Etiology and Pathophysiology

Surfactant deficiency (decreased production and secretion) is the primary cause of RDS. In the absence of pulmonary surfactant, significantly increased alveolar surface tension leads to atelectasis, and the ability to attain an adequate FRC is impaired. As a consequence of progressive injury to epithelial and endothelial cells from atelectasis (atelectrauma), volutrauma, ischemic injury, and oxygen toxicity, effusion of proteinaceous material and cellular debris into the alveolar spaces (forming the classic hyaline membranes ) further impairs oxygenation. Alveolar atelectasis, hyaline membrane formation, and interstitial edema make the lungs less compliant in RDS, so greater pressure is required to expand the alveoli and small airways. Additionally, compared with the mature infant, the highly compliant chest wall of the preterm infant offers less resistance to the natural tendency of the lungs to collapse. Thus, at end-expiration, the volume of the thorax and lungs tends to approach residual volume. Although surfactant is present in high concentrations in fetal lung homogenates by 20 wk of gestation, it does not reach the surface of the lungs until later. It appears in amniotic fluid between 28 and 32 wk. Mature levels of pulmonary surfactant are present usually after 35 wk of gestation.

The major constituents of surfactant are dipalmitoyl phosphatidylcholine (lecithin), phosphatidylglycerol, apoproteins (surfactant proteins SP-A, SP-B, SP-C, and SP-D), and cholesterol ( Fig. 122.2 ). With advancing GA, increasing amounts of phospholipids are synthesized and stored in type II alveolar cells ( Fig. 122.3 ). These surface-active agents are released into the alveoli, where they reduce surface tension and help maintain alveolar stability at end-expiration. Synthesis of surfactant depends in part on normal pH, temperature, and perfusion. Asphyxia, hypoxemia, and pulmonary ischemia, particularly in association with hypovolemia, hypotension, and cold stress, may suppress surfactant synthesis. The epithelial lining of the lungs may also be injured by high O ₂ concentrations and mechanical ventilation, thereby further reducing secretion of surfactant.

Atelectasis results in perfused but not ventilated alveoli, causing hypoxia. Decreased lung compliance, small tidal volumes, increased physiologic dead space, and insufficient alveolar ventilation eventually result in hypercapnia. The combination of hypercapnia, hypoxia, and acidosis produces pulmonary arterial vasoconstriction with increased right-to-left shunting through the foramen ovale and ductus arteriosus and within the lung itself. Progressive injury to epithelial and endothelial cells and formation of hyaline membranes further impairs oxygenation, leading to a vicious cycle of diminished surfactant production, worsening atelectasis, lung injury, and severe hypoxia ( Fig. 122.4 ).

Clinical Manifestations

Signs of RDS usually appear within minutes of birth, although they may not be recognized for several hours in larger premature infants, until rapid, shallow respirations become more obvious. A later onset of tachypnea should suggest other conditions. Some patients require resuscitation at birth because of intrapartum asphyxia or initial severe respiratory distress (especially with birthweight <1,000 g). Characteristically, tachypnea, prominent (often audible) expiratory grunting, intercostal and subcostal retractions, nasal flaring, and cyanosis are noted. Breath sounds may be normal or diminished with a harsh tubular quality, and on deep inspiration, fine crackles may be heard. The natural course of untreated RDS is characterized by progressive worsening of cyanosis and dyspnea. If the condition is inadequately treated, blood pressure may fall; cyanosis and pallor increase, and grunting decreases or disappears, as the condition worsens. Apnea and irregular respirations are ominous signs requiring immediate intervention. Untreated patients may also have a mixed respiratory-metabolic acidosis, edema, ileus, and oliguria. Respiratory failure may occur in infants with rapid progression of the disease. In most cases the signs reach a peak within 3 days, after which improvement is gradual. Improvement is often heralded by spontaneous diuresis and improved blood gas values at lower inspired O ₂ levels and/or lower ventilator support. Death can result from severe impairment of gas exchange, alveolar air leaks (pulmonary interstitial emphysema, pneumothorax), pulmonary hemorrhage, or intraventricular hemorrhage (IVH).

Diagnosis

The clinical course, chest x-ray findings, and blood gas values help establish the clinical diagnosis. On chest radiograph, the lungs may have a characteristic but not pathognomonic appearance that includes low lung volumes, a diffuse, fine reticular granularity of the parenchyma (ground-glass appearance), and air bronchograms ( Fig. 122.5 ). The initial x-ray appearance is occasionally normal, with the typical pattern developing during the 1st day. Considerable variation in radiographic findings may be seen, especially in infants who have already received treatment with surfactant replacement and/or positive pressure respiratory support; this variation often results in poor correlation between radiographic findings and the clinical course. Blood gas findings are characterized initially by hypoxemia and later by progressive hypoxemia, hypercapnia, and variable metabolic acidosis.

In the differential diagnosis, early-onset sepsis may be indistinguishable from RDS. In neonates with pneumonia, the chest radiograph may be identical to that for RDS. Clinical factors such as maternal group B streptococcal colonization with inadequate intrapartum antibiotic prophylaxis, maternal fever (>38.6°C) or chorioamnionitis, or prolonged rupture of membranes (>12 hr) are associated with an increased risk of early-onset sepsis. Although complete blood counts are neither sensitive nor specific in the diagnosis of early-onset sepsis, the presence of marked neutropenia has been associated with increased risk. Cyanotic congenital heart disease (in particular, total anomalous pulmonary venous return) can also mimic RDS both clinically and radiographically. Echocardiography with color-flow imaging should be performed in infants who show no response to surfactant replacement, to rule out cyanotic congenital heart disease as well as ascertain patency of the ductus arteriosus and assess pulmonary vascular resistance (PVR). Persistent pulmonary hypertension, aspiration (meconium, amniotic fluid) syndromes, spontaneous pneumothorax, pleural effusions, and congenital anomalies (pulmonary congenital airway malformations, pulmonary lymphangiectasia, diaphragmatic hernia, lobar emphysema) must be considered in patients with an atypical clinical course but can generally be differentiated from RDS through radiographic and other evaluations. Transient tachypnea may be distinguished by its shorter and milder clinical course and is characterized by low or no need for O ₂ supplementation.

Although rare, genetic disorders may contribute to respiratory distress. Abnormalities in surfactant protein B and C genes as well as a gene responsible for transporting surfactant across membranes, ABC transporter 3 ( ABCA3 ), are associated with severe and often lethal familial respiratory disease. Congenital alveolar proteinosis (congenital surfactant protein B deficiency) is a rare familial disease that manifests as severe and lethal RDS in predominantly term and near-term infants (see Chapter 434 ). In atypical cases of RDS, a lung profile (lecithin:sphingomyelin ratio and phosphatidylglycerol determination) performed on a tracheal aspirate can be helpful in establishing a diagnosis of surfactant deficiency. Other familial causes of neonatal respiratory distress (not RDS) include mucopolysaccharidosis, acinar dysplasia, pulmonary lymphangiectasia, and alveolocapillary dysplasia.

Prevention

Avoidance of unnecessary or poorly timed early (<39 wk GA) cesarean delivery or induction of labor, appropriate management of high-risk pregnancy and labor (including administration of antenatal corticosteroids), and prediction of pulmonary immaturity with possible in utero acceleration of maturation (see Chapter 119 ) are important preventive strategies. Antenatal and intrapartum fetal monitoring may decrease the risk of fetal asphyxia; asphyxia is associated with an increased incidence and severity of RDS.

Administration of antenatal corticosteroids to women before 37 wk gestation significantly reduces the incidence and mortality of RDS as well as overall neonatal mortality. Antenatal steroids also reduce (1) overall mortality, (2) admission to the neonatal intensive care unit (NICU) and need for/duration of ventilatory support, and (3) incidence of severe IVH, necrotizing enterocolitis (NEC), and neurodevelopmental impairment. Postnatal growth is not adversely affected. Antenatal corticosteroids do not increase the risk of maternal death, chorioamnionitis, or puerperal sepsis. Betamethasone and dexamethasone have both been used antenatally. Betamethasone may reduce neonatal death to a greater extent than dexamethasone.

Although classically, antenatal corticosteroids were reserved for preterm birth before 34 wk gestation, the administration of betamethasone before late preterm birth (34 ⁺⁰ to 36 ⁺⁶ wk gestation) significantly reduces the need for respiratory support and the incidence of severe respiratory complications. Therefore the American College of Obstetricians and Gynecologists (ACOG) recommends that for all women between 24 and 36 wk gestation who present in preterm labor and are likely to deliver a fetus within 1 wk, antenatal corticosteroid administration should be considered.

Treatment

The basic defect requiring treatment in RDS is inadequate pulmonary O ₂ -CO ₂ exchange. Basic supportive care (thermoregulatory, circulatory, fluid, electrolyte, and respiratory) is essential while FRC is established and maintained. Careful and frequent monitoring of heart and respiratory rates, Sa o ₂ , Pa o ₂ , Pa co ₂ , pH, electrolytes, glucose, hematocrit, blood pressure, and temperature are essential. Arterial catheterization is frequently necessary. Because most cases of RDS are self-limited, the goal of treatment is to minimize abnormal physiologic variations and superimposed iatrogenic problems. Treatment of infants with RDS is best carried out in the NICU.

Periodic monitoring of Pa o ₂ , Pa co ₂ , and pH is an important part of the management and is used to provide supportive care; if assisted ventilation is being used, such monitoring is essential. Oxygenation (S o ₂ ) should be assessed by continuous pulse oximetry. Capillary blood samples are of limited value for determining P o ₂ but may be useful for P co ₂ and pH monitoring. Monitoring of blood gas parameters and mean arterial blood pressure through an umbilical or peripheral arterial catheter is useful in managing the shock-like state that may occur during the initial hours in premature infants who have been asphyxiated or have severe RDS (see Fig. 121.3 ). The position of a radiopaque umbilical catheter should be checked radiographically after insertion (see Fig. 122.5 ). The tip of an umbilical artery catheter should lie at L3-L5 just above the bifurcation of the aorta or at T6-T10. The placement and supervision should be carried out by skilled and experienced personnel. Catheters should be removed as soon as patients no longer have any indication for their continued use—usually when an infant is stable and the fraction of inspired oxygen (F io ₂ ) is <40%.

Complications

Early provision of intensive observation and care of high-risk newborn infants can significantly reduce the morbidity and mortality associated with RDS and other acute neonatal illnesses. Antenatal corticosteroids, postnatal surfactant use, and improved modes of ventilation have resulted in low mortality from RDS (approximately 10%). Mortality increases with decreasing gestational age. Optimal results depend on the availability of experienced and skilled personnel, care in specially designed and organized regional hospital units, proper equipment, and lack of complications such as severe asphyxia, intracranial hemorrhage, or irremediable congenital malformation.

The most serious complications of endotracheal intubation are pulmonary air leaks , asphyxia from obstruction or dislodgment of the tube, bradycardia during intubation or suctioning, and the subsequent development of subglottic stenosis . Other complications include bleeding from trauma during intubation, posterior pharyngeal pseudodiverticula, need for tracheostomy, ulceration of the nares caused by pressure from the tube, permanent narrowing of the nostril as a result of tissue damage and scarring from irritation or infection around the tube, erosion of the palate, avulsion of a vocal cord, laryngeal ulcer, papilloma of a vocal cord, and persistent hoarseness, stridor, or edema of the larynx.

Measures to reduce the incidence of these complications include skillful intubation, adequate securing of the tube, use of polyvinyl ETTs, use of the smallest tube that will provide effective ventilation in order to reduce local pressure necrosis and ischemia, avoidance of frequent changes and motion of the tube in situ, avoidance of too frequent or too vigorous suctioning, and prevention of infection through meticulous cleanliness and frequent sterilization of all apparatus attached to or passed through the tube. The personnel inserting and caring for the ETT should be experienced and skilled in such care.

Extrapulmonary air leaks (pneumothorax, pneumomediastinum, pulmonary interstitial emphysema) are observed in 3–9% of extremely preterm infants with RDS (see Chapter 122.12 ). PPV with excessive inspiratory pressures (and therefore excessive tidal volumes), either during resuscitation at delivery or in the initial hours of mechanical ventilation, is a common risk factor, but air leaks can also occur in infants breathing spontaneously. Although the risk of air leak was increased in infants receiving a higher level of nCPAP (up to 8 cm H ₂ O) in the CPAP or Intubation at Birth (COIN) trial, subsequent trials have not demonstrated a similar effect.

Risks associated with umbilical arterial catheterization include vascular embolization, thrombosis, spasm, and vascular perforation; ischemic or chemical necrosis of abdominal viscera; infection; accidental hemorrhage; hypertension; and impairment of circulation to a leg with subsequent gangrene. Aortography has demonstrated that clots form in or about the tips of 95% of catheters placed in an umbilical artery. Aortic ultrasonography can also be used to investigate for the presence of thrombosis. Renovascular hypertension may occur days to weeks after umbilical arterial catheterization in a small proportion of neonates. Transient blanching of the leg may occur during catheterization of the umbilical artery. It is usually caused by reflex arterial spasm, the incidence of which is lessened by using the smallest available catheter, particularly in very small infants. The catheter should be removed immediately; catheterization of the other artery may then be attempted. Umbilical vein catheterization is associated with many of the same risks as umbilical artery catheterization. Additional risks are cardiac perforation and pericardial tamponade; improperly placed catheters in the portal vein can lead to thrombosis. The risk of a serious clinical complication resulting from umbilical catheterization is probably 2–5%.

Keywords

• bronchopulmonary dysplasia

• BPD

• chronic lung disease of prematurity

• alveolar simplification

• atelectrauma

• volutrauma

• pulmonary hypertension

• inhaled nitric oxide

• systemic corticosteroids

• dexamethasone

• hydrocortisone

• inhaled corticosteroids

• budesonide

• beclomethasone

• surfactant replacement therapy

• caffeine

• furosemide

• chlorothiazide

• sildenafil

• albuterol

• ipratropium

• cor pulmonale

Incidence

Bronchopulmonary dysplasia ( BPD , also known as chronic lung disease of prematurity ) is a clinical pulmonary syndrome that develops in the majority of extremely preterm infants and is defined by a prolonged need for respiratory support and supplemental oxygen. Almost 60% of infants born at ≤28 wk gestation will develop BPD, and the incidence of BPD increases inversely with gestational age. For infants born at the extreme of viability (22-24 wk), essentially 100% will develop BPD, the majority of whom will have moderate to severe disease. As neonatal care has improved and use of antenatal corticosteroids has become the standard of care, survival of infants born at the extreme of viability has improved, and BPD is encountered with increased prevalence. In the United States, an additional 10,000-15,000 new cases occur annually. Despite decades of experience, the incidence of BPD remains largely unchanged.

Etiology and Pathophysiology

BPD develops following preterm birth and the necessary life-supporting interventions (particularly mechanical ventilation and supplemental oxygen) that cause neonatal lung injury. As the limit of viability has been lowered by advances in neonatal care, the clinical syndrome associated with BPD has evolved. The clinical, radiographic, and lung histology of classic BPD described in 1967, before widespread use of antenatal corticosteroids and postnatal surfactant, was that of a disease of preterm infants who were more mature. During that era, infants born ≤30-32 wk gestation rarely survived. Infants who developed BPD demonstrated classic RDS initially, but the injurious mechanical ventilation and excessive supplemental oxygen required to support them resulted in a progressive, severe fibroproliferative lung disease. Improvements in respiratory care, as well as the introduction of surfactant and antenatal steroids, have allowed for gentle respiratory support strategies, and the need for excessive ventilator support and high percentages of inspired supplemental oxygen has decreased.

Despite a reduction in the fibroproliferative disease described previously, infants born in the modern era of neonatal care continued to require supplemental oxygen for prolonged periods. The new BPD is a disease primarily of infants with birthweight <1,000 g who were born at <28 wk gestation, some of whom have little or no lung disease at birth but over the 1st weeks of age experience progressive respiratory failure. Infants with the new BPD are born at a more immature stage of distal lung development, and lung histology demonstrates variable saccular wall fibrosis, minimal airway disease, abnormal pulmonary microvasculature development, and alveolar simplification. Although the etiology remains incompletely understood, the histopathology of BPD indicates interference with normal alveolar septation and microvascular maturation.

The pathogenesis of BPD is likely multifactorial, but pulmonary inflammation and lung injury are consistently observed. Alveolar collapse ( atelectrauma ) as a consequence of surfactant deficiency, together with ventilator-induced phasic overdistention of the lung ( volutrauma ), promotes lung inflammation and injury. Supplemental oxygen produces free radicals that cannot be metabolized by the immature antioxidant systems of very-low-birthweight (VLBW) neonates and further contributes to the injury. Pulmonary inflammation evidenced by infiltration of neutrophils and macrophages in alveolar fluid, as well as a host of proinflammatory cytokines, contributes to the progression of lung injury. Pre- and postnatal infection, excessive pulmonary blood flow via the patent ductus arteriosus (PDA), excessive administration of intravenous fluid, and pre- and postnatal growth failure are also significantly associated with the development of BPD. While the mechanisms are unclear, all likely promote lung injury by necessitating increased or prolonged respiratory support or interfering with lung repair. Regardless, the result is an interference with normal development of the alveolar-capillary unit and interference with normal gas exchange.