Chapter 39: Neonatal Respiratory Distress Syndrome and Sudden Infant Death Syndrome

Introduction to Neonatal RDS

Normal intrauterine lung development is comprised of stages featuring both cellular proliferation to increase total lung size, and cellular differentiation by which the airway and alveolar architectures are elaborated from primordial organ buds (Chaps. 2 and 37). By the time the fetus reaches normal term gestation (~38 weeks), there is ongoing alveolarization and normally the lungs are structurally and biochemically prepared for the transition to extrauterine function in gas exchange. Among the most profound changes in the lung at the time of birth are: (1) the replacement of fluid with gas in the airways, with consequent generation of alveolar surface tension forces that must be overcome; and (2) a fall in pulmonary vascular resistance, with consequent increase in pulmonary blood flow. These changes must occur over a relatively short time frame for normal pulmonary function. As an additional challenge, the newborn's lungs are surrounded by ribs and related thoracic structures that are considerably more compliant than in the adult, owing to their incomplete ossification. This greater thoracic compliance at birth limits the expansive traction that can be exerted by the chest wall on the lungs' visceral pleura, and thus alters the inherent equilibrium that defines FRC and the work of breathing (Chap. 6). Given these challenges, it is no surprise that respiratory failure is a major contributor to newborn morbidity and mortality.

By far, the most common cause of life-threatening respiratory disease in newborns is prematurity. Insufficient development and maturation of the type 2 surfactant-secreting epithelial cells leaves the preterm lung unprepared to overcome surface tension forces at the alveolar gas-fluid interface, as described by the law of Laplace (Chap. 5). The consequences of surfactant insufficiency in the preterm lung and the clinical treatment to overcome these consequences will be discussed in depth here. As these are elaborated below, the student should remember that surfactant dysfunction contributes to the pathogenesis of lung disease beyond the immediate postnatal period, such as ALI and ARDS (Chap. 28), emphasizing the broader implications of the concepts outlined in this chapter.

Historical Perspective: Failure of Oxygen Treatment

Before discussing the pathophysiology of RDS and the current modalities of treatment, it is useful first to consider why the historical mode of treatment, administration of oxygen, was by itself unsuccessful. Doing so will emphasize the particular consequences of diffuse alveolar collapse in the generation of intrapulmonary shunting. It will also emphasize consequences of open fetal cardiovascular channels to the generation of extrapulmonary shunting.

The hypoxemia seen in preterm newborn infants with RDS can be only partially and transiently overcome by placing the infant in high F_IO₂, such as that provided by an oxygen hood (Fig. 39.1). In more severe cases, the situation continues to worsen to a point at which even 100% O₂ cannot maintain normoxemia. The most dramatic example of the failure of O₂ therapy alone was the heroic effort to treat preterm infants in the early 1960s with hyperbaric oxygen. In order to increase O₂ delivery to the disease lungs beyond that supplied at atmospheric pressure, preterm infants with severe RDS were placed in a hyperbaric chamber. One infant treated in this manner was Patrick Bouvier Kennedy, son of then President John F. Kennedy of the United States. Unfortunately, the benefits of hyperbaric oxygen were transient at best in each of the reported infants (Fig. 39.2). Ultimately all of the reported infants in which hyperbaric oxygen was used, including Patrick Kennedy, died of hypoxemia.

Understanding the Pathophysiology of RDS

Unfortunately, the unstable and deteriorating clinical course of Patrick Kennedy was all too common in an era when methods to intervene successfully in RDS had not yet been developed. In subsequent decades, a vast amount of new information about the nature of pulmonary surfactant and the developmental biology of the type 2 cell emerged. These included an understanding of the timeline of their maturation and the normal composition of surfactant phospholipids and their associated proteins (Chaps. 5 and 10). The primary abnormality in neonatal RDS is a developmental deficiency in the production or secretion of pulmonary surfactant. The physical, laboratory, radiographic, and pathologic findings in neonatal RDS (Table 39.1) can each be understood based on the pivotal physiologic role of pulmonary surfactant (see Chaps. 5, 15, and 16). It is important to emphasize that neonatal RDS is not the same condition as the acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) discussed in Chap. 28. However, abnormalities of the surfactant system can contribute to the pathogenesis of both types of RDS, and there is considerable overlap in the clinical findings.

Presentation of Neonatal RDS

Recall from Chap. 5 that lung inflation and deflation can be modeled as a bubble at the end of a straw, whose expansion and contraction are governed by forces described by the law of Laplace. From this physiological principle, several consequences follow:

1. In the absence of a substance to lower surface tension forces, smaller alveoli collapse into larger ones;

2. Positive airway pressure applied during inspiration inflates such lungs to only small volumes with high critical opening pressures, (P_CO); and

3. Any open lung units are prone to premature collapse toward very low lung volumes during expiration.

Much of what presents as neonatal RDS in a premature infant follows as the predictable consequences of these principles, and can initiate or synergize with defective or suboptimal performances by other organ systems, including the heart.

Risk Factors for Developing Neonatal RDS

A number of specific factors have been identified that increase or decrease the likelihood of an infant developing RDS (Table 39.2). It is important to emphasize that a single risk factor such as prematurity is not 100% predictive, in part because it may be offset by factors like female gender, vaginal delivery, or prenatal glucocorticoids that reduce risk. These will be discussed in subsequent sections of this chapter.

As a cellular and biochemical process, surfactant synthesis is increased by glucocorticoids, thyroid hormone, and thyroid releasing hormone, but is decreased by increased levels of insulin or androgens. Surfactant secretion also is increased by β-adrenergic agonists and by endogenous catecholamines released during the physical stress of labor itself. Due to these and other variables (Table 39.2), not every preterm infant develops RDS while some infants of relatively late gestation do.

Physical Exam in Neonatal RDS

Tachypnea

Because patients with RDS move less air than normal with each inspiratory effort, that is, V_T is less, their respiratory frequency f must increase to maintain V̇_E. This extra work of breathing may eventually fatigue neonates, at which point their P_ao₂ falls and P_aco₂ may rise. Episodic apnea is also common in infants with RDS.

Grunting

A patient with RDS reflexively attempts to overcome the tendency for alveoli to collapse during expiration by partially closing the glottis to create an air stent (see Chaps. 25 and 30). The increased P_AW generated by expiring against a partially closed glottis stabilizes alveoli. Then as the patient opens the glottis to complete expiration and begin inspiration, the increased P_AW is suddenly released and causes an audible grunt. Students may visit Web site http://rale.ca/grunting.htm to hear a recording of grunting.

Chest Wall Retractions

Patients with RDS must generate more negative P_IP to move an equivalent volume of air into lungs that are less compliant (see Fig. 5.2). A large negative P_IP retracts inwardly the unossified chest wall during inspiration. While sternal and thoracic retractions can be seen in many infants, they are particularly prominent among premature ones whose chest walls are excessively compliant (Fig. 39.1).

Nasal Flaring

The nares are prone to inward collapse during inspiration if their patency is not maintained by contraction of the alea nares muscles. The neonate with RDS attempts to minimize nasal resistance to airflow during labored inspiration by reflexively contracting these muscles and thus presents with the clinical finding of nasal flaring.

Laboratory Findings in Neonatal RDS

P_aO₂ and/or S_aO₂ fall in infants with RDS for the same reasons that adults develop hypoxemia (Chaps. 8, 9, and 28). These are summarized in Table 39.3, and as for ARDS can be categorized by their responsiveness to only an increase in F_IO₂.

The neonate unable to maintain V̇_E due to fatigue, or whose functional V_D/V_T increases due to parenchymal hypoplasia, accumulates CO₂ and increases P_aCO₂. By Dalton's law, P_aO₂ declines proportionally (Chaps. 1 and 9). Many babies with RDS do not hypoventilate, but their hypoxemia can arise from diffusion block. Such a block may be caused by delayed progression to the alveolar stage (Chap. 2), yielding abnormally thick alveolar septa at birth that impede gas exchange (Chaps. 2 and 9). Diffusion block can also occur from accumulated proteinaceous material (hyaline membranes) within airways and airspaces, representing in part sluffed epithelial cells of the parenchyma (Chap. 26).

Perhaps an even greater contribution to neonatal hypoxemia is made by V̇_A/ Q̇ mismatch, due to the perfusion of underdeveloped, underventilated, or atelectatic alveoli (Chap. 8). Most significantly, each of these first three causes of hypoxemia can generally be treated by increasing the F_IO₂ and thus the P_AO₂ to the patient. The fourth cause of neonatal hypoxemia, that of persistent right-to-left shunting cannot be overcome by providing O₂ alone. Oxygen will not be effectively delivered to collapsed unventilated distal airways. If these distal airways remain perfused, there will be an "intrapulmonary" right to left shunt. Such a shunt cannot be overcome by increasing the concentration of inspired oxygen. The alveoli must be "recruited" into participation in gas exchange, for example, by providing distending pressures to overcome their surface tension forces, or providing surfactant to reduce their surface tension forces, to overcome this intrapulmonary shunt.

In addition to such an intrapulmonary right to left shunt, there are in newborn infants two important extrapulmonary sites where shunting can occur. These are the foramen ovale and the ductus arteriosus. A combination of factors in newborns with RDS, including hypoxemia and acidemia, can cause pulmonary vascular resistance to be elevated. If severe, shunting from right to left across fetal channels can occur. Treating this form of shunting depends upon lowering pulmonary vascular resistance.

As mentioned previously, the infant with RDS must breath rapidly to overcome a small functional V_T. If this response is insufficient, or if the infant tires, then P_aCO₂ will increase. Thus, hypoventilation can be an additional contributor to the hypoxemia seen in infants with RDS. The resulting respiratory acidosis (Chap. 17) will tend to increase pulmonary vascular resistance and lead to increased right-to-left shunting across fetal channels. In very severe cases, the C_aO₂ can become very low, systemic tissues may revert to anaerobic metabolism and an additional metabolic (lactic) acidosis can occur as well. It is this combination of problems that led to the very high mortality and resistance to O₂ therapy in the patient group described earlier.

Radiographic Findings in Neonatal RDS

The diffuse alveolar instability and atelectasis of neonatal RDS decreases TLC to an extent that may be apparent on the AP chest x-ray. In addition, collapsed lung is radiographically denser than normal, increasing the contrast between the parenchyma and conducting airways on film and making air bronchograms easily visible (Fig. 39.3; see Fig. 15.8). The contrast between open alveoli and those regions where collapse or consolidation have occurred yield a dark graininess against a lighter background on the chest film, the so-called "ground glass" appearance (compare with images in Chaps. 15, 24, and 28).

Lung Pathology in Neonatal RDS

Macroscopically, the lungs of an infant with neonatal RDS appear smaller than normal. However, they are not hypoplastic but rather underinflated. As expected, they have decreased compliance, that is, they require more gas pressure to inflate to a similar volume, and show a sharply increased P_CO compared to normal term lungs. Thus the neonatal RDS lung is also considered "stiff" like those of patients with ALI and ARDS (Chap. 28). The lungs of the patient with RDS can be inflated at normal pressures, however, with fluid rather than air, since surface tension forces are no longer in play and the tissue elastic recoil is normal (Chap. 5).

Microscopically the neonatal RDS lung often appears diffusely atelectatic, but with microscopic areas of overinflation that may be mistaken for emphysematous bullae (Chaps. 26 and 37). Under conventional staining with H&E, such lung sections show both fluid and proteinaceous debris that have leaked into the alveoli, comprising the hyaline membranes (Fig. 39.4) of diffuse alveolar damage (DAD) that are also seen in the lungs of some patients dying of ARDS (Chaps. 26 and 28).

Evolution of Treatments for Neonatal RDS

Oxygen

Supplemental oxygen remains an important modality in treating infants with RDS, as many of the contributors to hypoxemia in this condition respond to oxygen. Much of the blood that is perfusing the lungs of an infant with RDS does not encounter well-aerated alveoli for the reasons in Table 39.2. This results in a range of V̇_A/Q̇ mismatches <1.0 (Chap. 8). When V̇_A/Q̇ <1.0 but is less severe than a complete physiological shunt, increasing the P_AO₂ to such underventilated alveoli by raising the F_IO₂ or the total P_B enhances diffusion within them and thereby improves O₂ uptake. Thus O₂ remains an effective treatment for hypoxemia due to hypoventilation, diffusion block, or simple V̇_A/Q̇ mismatch (Table 39.2). Using O₂ to augment P_AO₂ also lowers pulmonary vascular resistance by attenuating any acute hypoxic pressor response (AHPR) due to alveolar hypoxia (see Fig. 8.3).

Correction of Right-to-Left Shunting

The various shunts that effectively allow blood to bypass the pulmonary microcirculation can occur within the lungs (an intrapulmonary shunt) or through the heart and associated large vessels (an extrapulmonary shunt) (Fig. 39.5). When such defects can only be corrected by surgical means, they are considered true anatomical shunts in the sense used earlier in this book (Chap. 9). Not unexpectedly, such extrapulmonary shunts represent a significant comorbidity in RDS.

Continuous Positive Airway Pressure

As in adults, anatomical or physiological shunt exceeding 40%-50% in a neonate is unresponsive to only increasing F_IO₂ and requires an air stent to recruit underinflated, never-opened, or atelectatic alveoli (Chaps. 9, 28, and 30). As in adults, this is most easily achieved with devices that produce positive airway pressure (P_AW) during at least the inspiratory phase and preferably throughout breathing. If intubation is unattainable or undesirable, CPAP appliances suitable for very small patients can increase P_AW by at least 5-8 cm H₂O (see Chap. 25). However, intubation permits a more comprehensive approach to mechanical ventilation of the neonate including a weight-appropriate V_T and PEEP. In this manner, an adequate V̇_E may be achieved while minimizing the infant's work of breathing. The staged instillation of exogenous surfactant emulsions over several inspiratory cycles is also facilitated by the availability of a previously positioned endotracheal tube (see below).

Prenatal Steroid Administration

Obstetricians quickly learned to exploit the maturational properties of glucocorticoids on cellular differentiation to accelerate fetal surfactant phospholipid synthesis in utero. Administering even 1-2 doses of dexamethasone, betamethasone, or related steroids to women at high risk for preterm delivery enhances neonatal survival and reduces RDS incidence by about 50%. Such glucocorticoids rapidly cross the placenta to increase fetal synthesis of surfactant phospholipids. Specific indications for prescribing prenatal steroids include:

1. Threatened premature labor earlier than 33-34 weeks' gestation if pulmonary maturity is unknown, that is, no L/S ratio or other assessment of surfactant system maturity has been made (Chap. 5); or

2. Documented immaturity by L/S ratio or other assessment, and delivery is not anticipated for at least 12 hours to ensure time for benefit to be realized.

Nitric Oxide

Inhaled NO gas relaxes smooth muscle in pulmonary resistance vessels, thereby reducing pulmonary vascular resistance (PVR) and normalizing V̇_A/Q̇ ratios in lung regions that might contribute to an increased physiological dead space (Chap. 8). Inhaled NO is not routine therapy for neonatal RDS and is only utilized in cases where the patient's PVR is excessive. Once inhaled NO dissolves in blood and tissues, it is rapidly degraded and thus has no appreciable systemic effects.

Surfactant Replacement

One of the most important accomplishments of pediatric pharmacotherapy is development and utilization of exogenous surfactants. While synthetic extracts consisting primarily of DPPC are effective, modified animal lung extracts that include surfactant proteins B and C are more successful (see Chap. 5). These preparations are instilled via an endotracheal tube, from which they rapidly disperse and spread into the peripheral airways. When performed properly, exogenous surfactant administration improves the physical, laboratory, radiographic, and pathologic findings in infants with RDS. Clinical trials also have demonstrated that exogenous surfactant therapy decreases both the morbidity and mortality of infants with RDS.

Prevention of Preterm Delivery

Because prematurity is the most important risk factor for RDS (Table 39.2), delaying preterm delivery is always attractive but not necessarily achievable. Without prenatal glucocorticoids, the incidence of RDS is ~ 60% in infants <30 weeks' gestation, declining to ~25% if at 30-34 weeks, and <5% among infants >34 weeks' gestation. Preventing preterm delivery is most often attempted with tocolytic agents, medications that block or slow intrauterine contractions.

Prognosis for Infants with Neonatal RDS

For reasons only partially understood, the endogenous surfactant system generally matures sufficiently within 72 hours of birth regardless of gestational age. Thereafter, additional surfactant replacement is rarely necessary or beneficial. However, surfactant deficiency is not the only abnormality of the premature lung. Thus, very premature infants usually require mechanical ventilatory support for a much longer period of time, despite the presence of adequate surfactant in distal airways and alveoli. With currently available therapies, the success rate for treating neonatal RDS is very high. Most of the remaining morbidity and mortality in infants with RDS relates to other complications of their prematurity, rather than to surfactant deficiency per se. Even with this caveat, the longterm outcomes of the vast majority of U.S. infants born prematurely are favorable, and continue to show improvement. Survival rates are correspondingly lower in all settings where maternal malnutrition, low socioeconomic status, and limited access to prenatal and postnatal care continue to exert pronounced negative effects.

SUDDEN INFANT DEATH SYNDROME (SIDS)

Introduction

SIDS is defined in the United States as "the sudden death of an infant <1 year of age which remains unexplained after a thorough case investigation, including performance of a complete autopsy, examination of the death scene, and review of the clinical history." Autopsies reveal no infection or other hidden health problems. SIDS is still the leading cause of neonatal death in this country, despite the "Back to Sleep" campaign that reduced SIDS from 1.2 deaths/1,000 live births in 1992 to 0.51 deaths/1,000 in 2006. The known and suspected risk factors for SIDS are shown in Table 39.4.

Many of these risk factors were addressed in the "Back to Sleep" campaign begun in 1992 which recommended that infants be placed in supine sleeping positions, in contrast to previous recommendations of prone sleeping positions. The number of SIDS cases has fallen dramatically by over 50% in the United States since that time (Fig. 39.6). Low socioeconomic status, premature birth, maternal smoking, and other factors remain prominent, however, as well as rebreathing asphyxial gases that contain abnormally high levels of carbon dioxide. Several genetic studies also show correlations with SIDS, including heritable arrhythmias (especially long QT syndrome), polymorphisms in the serotonin transporter gene, and others associated with development of the autonomic nervous system. It is suspected these genetic variants may interact with other risk factors.

Hypotheses Regarding SIDS Etiology

There have been few new ideas about the etiology of SIDS, and its cause is still completely unknown. Among the many factors that may initiate it, two considered to play pivotal roles involve: (1) central chemoreceptors and the arcuate nucleus; and (2) persistent fetal cardiorespiratory reflexes, notably the diving response (DR) and the laryngeal chemoreceptor reflex (LCR). These are considered separately below.

Changes in Transmitters/Receptors of the Ventral Medulla

Clinical correlations have been made between: (1) a diminished arcuate nucleus and SIDS, as well as reduced muscarinic (acetylcholine), kainate (glutamate), and lysergic acid (serotonin) receptors in the brainstems of SIDS victims (Fig. 39.7, upper panel); and (2) increased numbers of brainstem serotonergic neurons in SIDS victims (Fig. 39.7, lower panel). However, there is no proof that any of these correlations can explain SIDS-type disruptions in an infant's cardiorespiratory behavior.

Fetal Reflexes

Leiter and Böhm (2007) have suggested that neonates experience changes in the balance between excitatory adult reflexes that reduce SIDS risk and inhibitory fetal patterns that increase the risk of SIDS. They hypothesize that in some neonates, SIDS vulnerability is heightened and prolonged. The primary responses of the fetus to ambient hypoxia are bradycardia, reduced oxygen consumption, and redistribution of blood flow to essential organs, since respirations are not occurring in utero. Both the DR and the LCR induce bradycardia and sympathetic activation, as well as apnea. Both are considered conservative reflexes since a fetus can only respond to its environment, not change it. The rationale for these responses during hypoxic situations is that the organism must conserve its intrinsic oxygen stores for the two most essential organs, the heart and the brain.

The DR and LCR Reflexes

Stimulating the mucosa of the upper respiratory tract induces several autonomic adjustments to prevent noxious gases, liquids, or solids from entering the lungs. The DR is a collection of reflexes induced by stimulation of the nasal mucosa that naturally diving mammals utilize very efficiently. It begins with immediate apnea, an abrupt bradycardia, and selective peripheral vasoconstriction. It is present in all mammals including man, and is especially prominent in very young infants (Fig. 39.8). A key feature in relation to SIDS is that diving mammals do not breathe despite being hypercarbic and hypoxemic, and similar cardiorespiratory responses can be induced by nasal stimulation with CO₂. Juvenile rats can be trained to voluntarily submerge to traverse an underwater maze. During their entire underwater excursion, these animals show similar apnea, bradycardia, and increased systemic blood pressure reflecting abrupt peripheral vasoconstriction that reduces blood flow to most tissues (Fig. 39.9).

The LCR is induced by stimulating the mucosa around the glottis with water or acidic fluid (eg, vomitus) that causes cardiorespiratory responses similar to those initiated by the DR (Fig. 39.10). Like the DR, the LCR is most prominent in neonatal animals, is more prolonged in cases of hyperthermia, and is greater in anesthetized humans.