Background

Transient tachypnea of the newborn (TTN), often called type II RDS, is probably the most common respiratory disorder of newborns. The cause of TTN is unclear, but it is most likely related to delayed clearance of fetal lung liquid.15–29 During most births, approximately two-thirds of this fluid is expelled by thoracic squeeze in the birth canal; the rest is reabsorbed through the lymphatic vessels during initial breathing. These mechanisms are impaired in infants born by cesarean section or infants with incomplete development of the lymphatic vessels (preterm or small-for-gestational-age infants). The residual lung fluid causes an increase in airway resistance and an overall decrease in lung compliance. Because compliance is low, the infant must generate more negative pleural pressure to breathe. This process can result in hyperinflation of some areas and air trapping in others. Most infants with TTN are born at term without any specific predisposing factors in common. Mothers of neonates who have TTN tend to have longer labor intervals and a higher incidence of failure to progress in labor, which leads to cesarean delivery. In many cases, however, maternal history and labor and delivery are normal.

Clinical Manifestations

During the first few hours of life, infants with TTN breathe rapidly. Alveolar ventilation, as measured by arterial pH andPaCO₂, usually is normal. The chest radiographic findings, which may initially be indistinguishable from pneumonia, are hyperinflation, which is secondary to air trapping, and perihilar streaking. The perihilar streaking probably represents lymphatic engorgement. Pleural effusions may be evident in the costophrenic angles and interlobar fissures.

Treatment

Infants with TTN usually respond readily to a low FiO₂ by infant O₂ hood or nasal cannula. Infants requiring a higher FiO₂ may benefit from CPAP. Because the retention of lung fluid may be gravity-dependent, frequent changes in the infant’s position may help speed lung fluid clearance. Because TTN and neonatal pneumonia have similar clinical signs, intravenous administration of antibiotics should be considered for at least 3 days after appropriate culture samples are obtained. Mechanical ventilation is rarely needed, and when it is, this probably indicates a complication. Clearing of the lungs evident on a chest radiograph and with clinical improvement usually occurs within 24 to 48 hours. A few infants with TTN eventually have persistent pulmonary hypertension.

Background

Meconium aspiration syndrome (MAS) is a disease of term and near-term infants. It involves aspiration of meconium into the central airways of the lung. It usually is associated with perinatal depression and asphyxia.

Pathophysiology

Amniotic fluid consists mainly of fetal lung fluid, fetal urine, and transudate from the uterine wall. Meconium, the contents of the fetal intestine, occasionally is expelled from the fetus into the surrounding amniotic fluid. Meconium consists of mucopolysaccharides, cholesterol, bile acids and salts, intestinal enzymes, and other substances. Meconium normally is not passed until after delivery.³⁰ Infants who have marked perinatal depression or perinatal asphyxia may pass meconium in utero. The pathophysiologic control mechanisms for the passage of meconium in utero are not completely understood. It is widely accepted that infants can have meconium aspiration in utero. Amniotic fluid stained with meconium is found in approximately 12% of all births.³⁰ Meconium-stained amniotic fluid is rare among infants of less than 37 weeks’ gestational age. The clinical syndrome develops in 2 of every 1000 infants. Of infants with inhaled meconium, 95% clear their lungs spontaneously.³⁰Amniotic fluid infusion into the uterus before the delivery of infants with meconium-stained fluid has been shown to improve neonatal outcomes.^31,32

For many years, the aspirated meconium itself was considered the primary cause of MAS. More recent evidence suggests that the real causative agent is fetal asphyxia that precedes aspiration.²³ Fetal asphyxia causes pulmonary vasospasm and hyperreactivity of the vasculature, which lead to persistent pulmonary hypertension.

MAS involves three primary problems: pulmonary obstruction, lung tissue damage, and pulmonary hypertension.³³ Obstruction occurs because of plugging of the airways with particulate meconium. This obstruction often is of the ball-valve type, which allows gas entry but prevents gas exit. Ball-valve obstruction causes air trapping and can lead to volutrauma (Figure 31-3). The lung tissue injury caused by MAS is chemical pneumonitis. Additionally, there are various chemical effects, inflammatory responses, cytokine and chemokine activations, complement activation, and phospholipase A₂ activation.^33–37 Persistent pulmonary hypertension with intracardiac and extracardiac right-to-left shunting frequently complicates MAS.³⁰

Clinical Manifestations

Before birth, thick meconium, fetal tachycardia, and absent fetal cardiac accelerations during labor are evidence that the fetus is at high risk of MAS.³⁸ After delivery, if the infant has a low umbilical artery pH, an Apgar score less than 5, and meconium aspirated from the trachea, intensive care and close observation for MAS are warranted. Infants with MAS typically have gasping respirations, tachypnea, grunting, and retractions. The chest radiograph usually shows irregular pulmonary densities, which represent areas of atelectasis, and hyperlucent areas, which represent hyperinflation secondary to air trapping (Figure 31-4). Arterial blood gases typically show hypoxemia with mixed respiratory and metabolic acidosis. In the most severe cases, there is right-to-left shunting and persistent pulmonary hypertension.³⁰

Treatment

It is no longer recommended that vigorous infants with meconium-stained fluid be intubated and suctioned.31,39–41 However, it is important that an endotracheal tube be inserted immediately in severely depressed infants with thick meconium, and suction should be applied directly to the endotracheal tube.⁴⁰ The endotracheal tube is removed and inspected for meconium. If meconium is present, the procedure is repeated with a new endotracheal tube until no further meconium is aspirated or until two to four aspirations have been performed. The endotracheal tube should be left in place, and mechanical ventilation should be started. For prevention of hypoxemia, a flow of warmed 100% O₂ should be blown across the infant’s face during the aspiration efforts. No evidence suggests an improved outcome because of endotracheal suctioning in the care of infants who have meconium and are vigorous and would not otherwise require intubation.^42,43 There is evidence that tracheal lavage with dilute surfactant improves the clinical course and outcome of infants with MAS.^44–46

If the infant’s condition worsens, CPAP or mechanical ventilation may be indicated. CPAP is indicated if the primary problem is hypoxemia. By distending the small airways, CPAP can sometimes overcome the ball-valve obstruction and improve both oxygenation and ventilation. If respiratory acidosis is severe or clinical assessment indicates excessive work in breathing, mechanical ventilation should be started. Figure 31-3 shows the ball-valve effect. At rest, the airway lumen is partially obstructed. With inspiration, negative intrathoracic pressure opens the airway and relieves the obstruction. Gas enters and expands the alveoli. With expiration, intrathoracic pressure changes to a positive force, which narrows the airway and causes total occlusion. Gas cannot be expelled and is trapped within the alveoli. It is difficult to provide ventilation to infants with severe MAS. These infants often retain CO₂ and need increased ventilator support. Because of high airways resistance, the lungs have a long time constant. High ventilator rates and pressures increase the risk of air trapping and volutrauma.

Evidence suggests that both HFV and synchronous intermittent mechanical ventilation decrease the risk of air leak.⁴⁷ Various studies have shown improvement in MAS with the use of HFV and surfactant.⁴⁸ Nitric oxide has become a major adjunct in the management of persistent pulmonary hypertension.⁴⁹ Corticosteroids have not yet been shown to improve outcomes for infants with MAS.⁵⁰ High mean airway pressures may worsen pulmonary hypertension and aggravate right-to-left cardiac shunting.³⁸

Background

Infants, especially preterm infants, with severe respiratory failure in the first few weeks of life may develop a chronic pulmonary condition called bronchopulmonary dysplasia (BPD). BPD is a complex disease that is poorly defined.51–54 Historical definitions have included radiographic patterns and the requirement for supplemental O₂ at fixed time points in the infant’s life. Immaturity, genetics, malnutrition, O₂ toxicity, and mechanical ventilation all have been implicated in the origin of BPD.^51,55–62

Pathophysiology

The development of BPD is complex and involves many pathways. The initiating factors are related to atelectrauma (lung collapse) and volutrauma (large tidal volume [V_T]). Factors such as hyperoxia and hypoxia, mechanical forces, vascular maldevelopment, inflammation, nutrition, and genetics contribute to the abnormal development of the lung and lead to BPD.56,59,63–67 Atelectrauma is a term coined to describe loss of alveolar volume that is both a consequence and a cause of lung injury. Volutrauma is the term used to describe local overinflation (and stretch) of airways and alveoli. Atelectrauma leads to derecuitment (e.g., areas of alveolar collapse) of the lung. Volutrauma leads to damage to airways, pulmonary capillary endothelium, alveolar and airway epithelium, and basement membranes. The combination of atelectrauma and volutrauma synergistically increases lung injury.

Both atelectrauma and volutrauma cause a need for increased supplemental O₂ concentrations. This use of supplemental O₂ leads to overproduction of superoxide, hydrogen peroxide, and perhydroxyl radicals. Preterm infants are particularly susceptible to O₂ radicals because the antioxidant systems develop in the last trimester of pregnancy. Prolonged hyperoxia begins a sequence of lung injury that leads to inflammation, diffuse alveolar damage, pulmonary dysfunction, and death.

The response of the lungs to the combination of trauma and O₂ toxicity is the production and release of soluble mediators. These mediators probably are released from granulocytes residing in the lung. The release of these mediators can injure the alveolar-capillary barrier and induce an inflammatory response.⁶² A “new” BPD is being described that shows decreased alveolarization rather than the prominent airway damage of the “old” BPD. This change in the pathologic characteristics of BPD is thought to be related to improvements in ventilator management, the use of surfactant, and processes that interrupt alveolar development (e.g., postnatal steroid therapy).^54,68–70 Some authors speculate that the “new” BPD and “old” BPD are the same disease. The difference is that clinicians are better at performing mechanical ventilation in infants and do less damage to the airway compared with 20 years ago.⁷¹

Clinical Manifestations

BPD has various clinical manifestations. Some very immature infants may start with little or no O₂ requirement and little or no mechanical ventilation requirement. Progressive respiratory distress develops at approximately 2 to 3 weeks of life, and then the infant needs O₂ and mechanical ventilation. Other immature infants may begin with pneumonia or sepsis and need very high levels of O₂ and mechanical ventilation. In either of these scenarios, progressive vascular leakage and areas of atelectasis and emphysema develop in the lungs, and progressive pulmonary damage occurs. The chest radiograph in severe disease shows areas of atelectasis, emphysema, and fibrosis diffusely intermixed throughout the lung (Figure 31-5).^67,72 Arterial blood gas measurements reveal varying degrees of hypoxemia and hypercapnia secondary to airway obstruction, air trapping, pulmonary fibrosis, and atelectasis. There is a marked increase in airway resistance with an overall decrease in lung compliance.

Treatment

The best management of BPD is prevention. Prevention of atelectrauma and volutrauma begins in the delivery room. Establishment of an optimal FRC without overstretching the lung requires careful attention to detail in providing end-tidal pressure and avoiding large V_T. Surfactant should be delivered early in the course of treatment.

Treatment of infants with BPD involves steps to minimize additional lung damage and prevent pulmonary hypertension and cor pulmonale. Infants with severe disease may be dependent on supplemental O₂ or mechanical ventilation for months and have symptoms of airway obstruction for years. Therapy usually is supportive throughout the course of the disease. An infant with BPD is given respiratory support as needed. Supplemental O₂ can help decrease the pulmonary hypertension that is common with BPD.

Multiple pharmacologic treatments have been advocated for infants with BPD.⁷³ Diuretics are given as needed to decrease pulmonary edema; antibiotics are given to manage existing pulmonary infection.⁷⁴ Chest physical therapy may help mobilize secretions and prevent further atelectasis. Bronchodilator therapy may be useful in decreasing airway resistance.⁷⁵ Steroid therapy with dexamethasone can produce substantial short-term improvement in lung function, often allowing rapid weaning from ventilatory support. However, steroid therapy has little effect on long-term outcome such as mortality and duration of O₂ therapy.^76,77 Steroid therapy also has been implicated in decreased alveolarization and increased developmental delay.⁷⁸ Although steroids are still given in clinical practice, they should be used cautiously and only after the risks have been thoroughly explained to the parents.

Background

Apnea of prematurity is a common, controllable disorder among premature infants. It usually resolves over time.79–84 Premature infants frequently have periodic respiration, which comprises sequential short apneic episodes of 5 to 10 seconds followed by 10 to 15 seconds of rapid respiration. Apneic spells are abnormal if (1) they last longer than 15 seconds; or (2) they are associated with cyanosis, pallor, hypotonia, or bradycardia.

If no effort to breathe occurs during a spell, the apnea is called central apnea. If breathing efforts occur, but obstruction prevents airflow, the apnea is termed obstructive. Mixed apnea is a combination of the central and obstructive types that starts as obstructive apnea and then develops into central apnea.79–83,85

Etiology

Premature infants have immature control of respiratory drive in response to oxygen and carbon dioxide. In mature animals, an increase in alveolar PaCO₂ elicits an increase in V_T and respiratory rate. A decrease in FiO₂ below room air also triggers an increase in V_T. Conversely, in premature animals, an increase in PaCO₂ temporarily increases V_T but does not increase respiratory rate. A decrease in FiO₂ below room air decreases V_T and respiratory rate. This effect can lead to apnea in a premature infant. Several factors in addition to prematurity can cause apnea in infants. Table 31-2 summarizes the potential causes, associated signs, and diagnostic indicators.⁸⁶

Treatment

Infants with apnea need continuous monitoring of heart and respiratory rates. Continuous noninvasive monitoring of oxygenation by transcutaneous electrode or pulse oximetry is recommended. Most apneic incidents can be quickly terminated with gentle mechanical stimulation, such as picking the infant up, flicking the sole of the foot, or rubbing the skin.79,81,82,85,87 If the cause of apnea is not prematurity, treatment must be directed at resolving the underlying condition. Table 31-3 outlines current treatment strategies for infants with apnea.⁸⁶ Apnea secondary to prematurity responds well to methylxanthines, especially theophylline and caffeine.^82,85,87 These agents stimulate the central nervous system and increase the infant’s responsiveness to CO₂. For infants with apnea that is refractory to treatment with theophylline, doxapram can be used.^88–90 However, doxapram is delivered by continuous infusion and has multiple toxicities.

CPAP can also be used to manage infant apnea.⁹¹ Although the mechanism of action is not established, CPAP probably increases FRC and improves arterial partial pressure of oxygen (PaO₂) and PaCO₂. CPAP may also stimulate vagal receptors in the lung, increasing the output of the brainstem respiratory centers. Severe or recurrent apnea that is unresponsive to these interventions may necessitate mechanical ventilatory support.

As the respiratory control mechanisms mature, apnea of prematurity normally resolves without intervention. Apneic spells begin to disappear by week 37 to 44 of postmenstrual age with no apparent long-term effects. Infants who have apnea of prematurity are not at higher risk of sudden infant death syndrome (SIDS) than other infants.

Apnea monitoring can allow infants who are otherwise ready for discharge but still having occasional episodes of apnea to go home.79,81,85,92–95 However, the presence of a home apnea monitor is a significant inconvenience to the family. Home monitors lack the sophisticated filtering systems of hospital monitors, and they have very frequent false alarms.

Background

Persistent pulmonary hypertension of the newborn (PPHN) is a complex syndrome with many causes.⁹⁶ The common denominator in PPHN is a return to fetal circulatory pathways, usually because of elevated PVR. This condition results in further right-to-left shunting, severe hypoxemia, and metabolic and respiratory acidosis.

Pathophysiology

In the uterus, the fetus does not use the lungs as a gas exchange organ. PVR is high, and systemic vascular resistance (SVR) is low. This condition produces a PVR/SVR ratio greater than 1. A fetus has two anatomic shunts that are not present in older infants, children, or adults: foramen ovale and ductus arteriosus. With a PVR/SVR ratio greater than 1 and the anatomic shunts, blood flow bypasses the lung either at the atrial level (foramen ovale) or at the pulmonary artery (ductus arteriosus). Intrauterine total pulmonary blood flow and systemic arterial O₂ saturation are low.

In the transition to extrauterine life, PVR decreases owing to gas filling of the lung and increasing PaO₂ in the pulmonary venous circulation. SVR increases with the removal of the placenta from the circulation, and this makes the PVR/SVR ratio less than 1. If PVR does not decrease to allow the PVR/SVR ratio to become less than 1, the infant has PPHN.

There are three fundamental types of PPHN: vascular spasm, increased muscle wall thickness, and decreased cross-sectional area of pulmonary vessels.⁹⁷ Vascular spasm is an acute event that can be triggered by many different conditions, including hypoxemia, hypoglycemia, hypotension, and pain. Increased muscle wall thickness is a chronic condition that develops in utero in response to several different etiologic factors, including chronic fetal hypoxia, increased pulmonary blood flow (e.g., intrauterine closure of the ductus arteriosus), and pulmonary venous obstruction (e.g., total anomalous pulmonary venous return with obstructed below-diaphragm return). Decreased cross-sectional area is related to hypoplasia of the lungs and occurs with congenital diaphragmatic hernia, Potter sequence (absent kidneys), and oligohydramnios syndromes (decreased amniotic fluid).

Clinical Manifestations

PPHN should be suspected when an infant has rapidly changing O₂