124: Respiratory Distress Syndrome

Respiratory distress syndrome (RDS) was previously called hyaline membrane disease. The Vermont Oxford Network definition for RDS requires that babies have:

1. An arterial oxygen tension (Pao₂) <50 mm Hg and central cyanosis in room air, a requirement for supplemental oxygen to maintain Pao₂>50 mm Hg, or a requirement for supplemental oxygen to maintain a pulse oximeter saturation over 85 %.

2. A characteristic chest radiographic appearance (uniform reticulogranular pattern to lung fields with or without low lung volumes and air bronchogram) within the first 24 hours of life. The clinical course of the disease varies with the size of the infant, severity of disease, use of surfactant replacement therapy, presence of infection, degree of shunting of blood through the patent ductus arteriosus (PDA), and whether or not assisted ventilation was initiated.

Incidence of RDS is ∼91% at 23–25 weeks' gestation, 88% at 26–27 weeks' gestation, 74 % at 28–29 weeks' gestation, and 52% at 30–31 weeks' gestation. The incidence and severity of RDS are expected to decrease after the increase in use of antenatal steroids in recent years. After the introduction of exogenous surfactant, the survival from RDS is at >90%. During the surfactant era, RDS accounts for <6% of all neonatal deaths.

Surfactant deficiency is the primary cause of RDS, often complicated by an overly compliant chest wall. Both factors lead to progressive atelectasis and failure to develop an effective functional residual capacity (FRC). Surfactant is a surface-active material produced by airway epithelial cells called type II pneumocytes. This cell line differentiates, and surfactant synthesis begins at 24–28 weeks' gestation. Type II cells are sensitive to and decreased by asphyxial insults in the perinatal period. The maturation of this cell line is delayed in the presence of fetal hyperinsulinemia. The maturity of type II cells is enhanced by the administration of antenatal corticosteroids and by chronic intrauterine stress such as pregnancy-induced hypertension, intrauterine growth restriction, and twin gestation. Surfactant, composed chiefly of phospholipid (75%) and protein (10%), is produced and stored in the characteristic lamellar bodies of type II pneumocytes. This lipoprotein is released into the airways, where it functions to decrease surface tension and maintain alveolar expansion at physiologic pressures.

1. Lack of surfactant. In the absence of surfactant, the small airspaces collapse; each expiration results in progressive atelectasis. Exudative proteinaceous material and epithelial debris, resulting from progressive cellular damage, collect in the airway and directly decrease total lung capacity. In pathologic specimens, this material stains typically as eosinophilic hyaline membranes lining the alveolar spaces and extending into small airways.

2. Presence of an overly compliant chest wall. In the presence of a chest wall with weak structural support secondary to prematurity, the large negative pressures generated to open the collapsed airways cause retraction and deformation of the chest wall instead of inflation of the poorly compliant lungs.

3. Decreased intrathoracic pressure. The infant with RDS who is <30 weeks' gestational age often has immediate respiratory failure because of an inability to generate the intrathoracic pressure necessary to inflate the lungs without surfactant.

4. Shunting. The presence or absence of a cardiovascular shunt through a PDA or foramen ovale, or both, may change the presentation or course of the disease process. Shortly after birth, the predominant shunting is right to left across the foramen ovale into the left atrium, which may result in venous admixture and worsening hypoxemia. After 18–24 hours, left-to-right shunting through the PDA may become predominant as a result of falling pulmonary vascular resistance, leading to pulmonary edema and impaired alveolar gas exchange. Unfortunately, this usually occurs when the infant is starting to recover from RDS and can be aggravated by surfactant replacement therapy.

Table 124–1 lists factors that increase or decrease the risk of RDS.

1. History. The infant is often preterm or has a history of asphyxia in the perinatal period. Infants have some respiratory difficulty at birth, which becomes progressively more severe. The classic worsening of the atelectasis seen on chest radiograph and increasing oxygen requirement for these infants have been greatly modified by the availability of exogenous surfactant therapy and effective mechanical ventilatory support.

2. Physical examination. The infant with RDS exhibits tachypnea, grunting, nasal flaring, and retractions of the chest wall. The infant may have cyanosis in room air. Grunting occurs when the infant partially closes the vocal cords to prolong expiration and develop or maintain some FRC. This mechanism actually improves alveolar ventilation. The retractions occur and increase as the infant is forced to develop high transpulmonary pressure to reinflate atelectatic air spaces.

1. Chest radiograph. An anteroposterior chest radiograph should be obtained for all infants with respiratory distress of any duration. The typical radiographic finding of RDS is a uniform reticulogranular pattern, referred to as a ground-glass appearance, accompanied by peripheral air bronchograms (see Figure 11–13). During the clinical course, sequential radiographs may reveal air leaks secondary to mechanical ventilatory intervention as well as the onset of changes compatible with bronchopulmonary dysplasia/chronic lung disease (BPD/CLD) (see Figure 11–17).

2. Laboratory studies

   1. Blood gas sampling. Essential in the management of RDS. Usually, intermittent arterial sampling is performed. Although there is no consensus, most neonatologists agree that arterial oxygen tensions of 50–70 mm Hg and arterial carbon dioxide tensions of 45–60 mm Hg are acceptable. Most would maintain the pH at or above 7.25 and the arterial oxygen saturation at 85–93%. In addition, continuous transcutaneous oxygen and carbon dioxide monitors or oxygen saturation monitors, or both, are proving valuable in the minute-to-minute monitoring of these infants.

   2. Sepsis workup. A partial sepsis workup, including complete blood cell count and blood culture, should be considered for each infant with a diagnosis of RDS because early-onset sepsis (eg, infection with group B Streptococcus) can be indistinguishable from RDS on clinical grounds alone.

   3. Serum glucose levels. May be high or low initially and must be monitored closely to assess the adequacy of dextrose infusion. Hypoglycemia alone can lead to tachypnea and respiratory distress.

   4. Serum electrolyte levels and calcium. Should be monitored every 12–24 hours for management of parenteral fluids. Hypocalcemia can contribute to more respiratory symptoms and is common in sick, nonfed, preterm, or asphyxiated infants.

3. Echocardiography. A valuable diagnostic tool in the evaluation of an infant with hypoxemia and respiratory distress. It is used to confirm the diagnosis of PDA as well as to document response to therapy. Significant congenital heart disease can be excluded by this technique as well.

1. Prevention

   1. Antenatal corticosteroids. Treatment with antenatal corticosteroids is associated with an overall reduction in neonatal death, RDS, intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), respiratory support, intensive care admissions, and systemic infections in the first 48 hours of life. A single course of antenatal steroids is recommended between 24 and 34 weeks of gestation to all women at risk of preterm delivery within 7 days. A single course should be administered to women with premature rupture of membranes before 32 weeks of gestation to reduce the risks of RDS, perinatal mortality, and other morbidities. The efficacy of corticosteroid use at 32–33 completed weeks for preterm prelabor rupture of membranes is unclear based on current evidence, but treatment may be beneficial, especially if pulmonary immaturity is documented. Antenatal corticosteroids should be considered for threatened preterm birth at 22–23 weeks of gestation. Antenatal corticosteroid exposure reduced improved survival of extremely preterm infants. Antenatal treatment with corticosteroids at 34–36 weeks of pregnancy has not reduced the risk of respiratory morbidity in neonates. The optimal treatment to delivery interval is >24 and <7 days after the start of steroid treatment. A second course should be considered if the risk from RDS is felt to outweigh the uncertainty about possible long-term adverse effects. The recommended glucocorticoid regimen consists of the administration to the mother of two 12-mg doses of betamethasone given intramuscularly 24 hours apart. Dexamethasone is not recommended because of increased risk for cystic periventricular leukomalacia among very premature infants exposed to the drug prenatally.

   2. Preventive measures. Several preventive measures may improve the survival of infants at risk for RDS and include antenatal ultrasonography for more accurate assessment of gestational age and fetal well-being, continuous fetal monitoring to document fetal well-being during labor or to signal the need for intervention when fetal distress is discovered, tocolytic agents that prevent and treat preterm labor, and assessment of fetal lung maturity before delivery (lecithin-to-sphingomyelin ratio and phosphatidylglycerol; or amniotic fluid lamellar bodies, see Chapter 1) to prevent iatrogenic prematurity.

2. Surfactant replacement. (See also Chapter 8.) Now considered a standard of care in the treatment of intubated infants with RDS. Since the late 1980s, >30 randomized clinical trials involving >6000 infants have been conducted. Systematic reviews of these trials demonstrate that surfactant, whether used prophylactically in the delivery room or in the treatment of established disease, leads to a significant decrease in the risk of pneumothorax and the risk of death. These benefits were observed in both the trials of natural surfactant extracts and synthetic surfactants. Prophylactic surfactant replacement to prevent RDS in infants born at <31 weeks' gestation has reduced the risk of death or BPD/CLD but may result in some infants being intubated and receiving treatment unnecessarily. A recent consensus statement recommends surfactant prophylaxis (within 15 minutes of birth) to almost all infants <26 weeks' gestation. Prophylaxis should also be administered to all preterm infants with RDS who require delivery-room intubation for stabilization. Early rescue surfactant should be administered to preterm babies with an evidence of RDS. The effect of surfactant therapy is better the earlier in the course of RDS it is given. A second, sometimes a third dose of surfactant should be administered in cases with ongoing evidence of RDS (ie, persistent need of mechanical ventilation and oxygen supplementation).

   Natural (derived from animal lungs) surfactant preparations are better than synthetic (protein-free) at reducing pulmonary air leaks. Natural surfactants are therefore the treatment of choice. Trials comparing natural bovine surfactants, given prophylactically or as rescue therapy, have shown similar outcomes. Trials comparing bovine and porcine-derived surfactants have shown a more rapid improvement in oxygenation in the latter. A better survival has been demonstrated in a meta-analysis comparing a 200-mg/kg dose of poractant alfa with 100 mg/kg of beractant, or 100 mg/kg poractant alfa, for rescue treatment of moderate to severe RDS. Poractant alfa treatment for RDS was in a retrospective study associated with a significantly reduced likelihood of death, when compared with calfactant, and a trend toward reduced mortality when compared with beractant.

   Mechanical ventilation can be avoided by using the INSURE (Intubate-Surfactant-Extubate to CPAP [continuous positive airway pressure]) technique when surfactant is administered. This has reduced need for mechanical ventilation and development of BPD/CLD in randomized trials. Immediate (or early) extubation to noninvasive respiratory support (CPAP or nasal intermittent positive ventilation) following surfactant administration should be considered in otherwise stabile infants.

   Currently, long-term follow-up studies have not shown significant differences between surfactant-treated patients and nontreated control groups with regard to PDA, IVH, retinopathy of prematurity, NEC, and BPD/CLD. Evidence exists that the length of stay on mechanical ventilation and total ventilator days have been reduced with the use of surfactant at all gestational age levels, even with the increase of extremely low birthweight infants. A dramatic fall in deaths from RDS began in 1991. This probably reflected the introduction of surfactant replacement therapy. In long-term follow-up studies, no adverse effects attributable to surfactant therapy have been identified.

3. Respiratory support

   1. Endotracheal intubation and mechanical ventilation. Mainstays of therapy for infants with RDS in whom apnea or hypoxemia with respiratory acidosis develops. Mechanical ventilation (MV) modes include conventional, such as intermittent positive pressure ventilation (IPPV), and high-frequency oscillatory ventilation (HFOV). Ventilators with the capacity to synchronize respiratory effort may generate less inadvertent airway pressure and lessen barotrauma. Ventilator settings should be adjusted frequently to maintain the lowest possible pressures and inspired oxygen concentrations in an attempt to minimize damage to parenchymal tissue. HFOV may be beneficial as a rescue therapy in infants with respiratory failure on IPPV. Rescue HFOV reduces pulmonary air leaks but is associated with an increased risk of IVH. Insufficient evidence exists to recommend the routine use of HFOV instead of conventional ventilation for preterm infants with lung disease. Hypocapnia is associated with increased risks of BPD/CLD and periventricular leukomalacia and should therefore be avoided. To minimize duration of MV, weaning from MV should be started as soon as satisfactory gas exchange is achieved. Caffeine should be routinely used for very preterm neonates with RDS to augment extubation.

   2. Continuous positive airway pressure (CPAP) and nasal synchronized intermittent mandatory ventilation (SIMV). Nasal CPAP (NCPAP) or nasopharyngeal CPAP (NPCPAP) can be used early to delay or prevent the need for endotracheal intubation and mechanical ventilation. CPAP treatment is recommended to be started from birth in all infants at risk of RDS, as those born at <30 weeks' gestation. In this way some infants with RDS can be managed without surfactant replacement. By not using surfactant, however, the risk of pneumothorax is increased. Use of NCPAP or NPCPAP on extubation after mechanical ventilation decreases the chance of reintubation, when at least 5 cm H₂O pressure is applied. Nasal SIMV is a potentially useful way of augmenting NCPAP. The ability to synchronize the ventilator breaths with the infant's own respiratory cycle has made this mode of ventilation feasible. In 3 trials, nasal SIMV has reduced the incidence of symptoms of extubation failure when compared with NCPAP. Short binasal prongs should be used instead of a single prong.

   3. Humidified high-flow nasal cannula system. This has been introduced to neonatal respiratory care as a way to provide positive distending pressure, even comparable to NCPAP, to a neonate with respiratory distress. It aims to maximize patient tolerance by using heated, humidified gas flow (≥ 1 L/min). Studies comparing high-flow nasal cannula with nasal SIMV for RDS are going on.

   4. Complications. Pulmonary air leaks, such as pneumothorax, pneumomediastinum, pneumopericardium, and pulmonary interstitial emphysema, may occur (see Chapter 81). Chronic complications include respiratory problems such as BPD/CLD (see Chapter 84) and tracheal stenosis.

4. Fluid and nutritional support. In the very ill infant, it is possible to maintain nutritional support with parenteral nutrition for an extended period. Full parenteral nutrition and minimal enteral feeding can be initiated on the first day of life. Careful fluid balance should, however, be maintained. The specific needs of preterm and term infants are becoming better understood, and the nutrient preparations available reflect this understanding (see Chapters 9 and 10).

5. Antibiotic therapy. Antibiotics that cover the most common neonatal infections are usually begun initially.

6. Sedation. Commonly used to control ventilation in these sick infants. Morphine, fentanyl, or lorazepam may be used for analgesia as well as sedation, but there is significant controversy surrounding such treatment. Reported advantages of treatment include improved ventilator synchrony and pulmonary function. Decreased adverse long-term neurologic sequelae have been suggested. Neuroendocrine responses to mechanical ventilation are alleviated by opioid treatment, which may be beneficial in the long term. However, clinicians should consider adverse effects of medication, especially opioids, including hypotension with morphine and chest wall rigidity with fentanyl. Tolerance, dependence, and withdrawal occur. In addition, pharmacologic treatment does not decrease adverse sequelae, at least in the short term. The most significant gaps in knowledge include the inability to assess chronic pain in this population and the long-term effects of treatment. Minimal handling to avoid pain is an important means to decrease need for pain management in ventilated infants. Muscle paralysis with pancuronium for infants with RDS remains controversial. Sedation might be indicated for infants who “fight” the ventilator and exhale during the inspiratory cycle of MV. This respiratory pattern may increase the likelihood of complication such as air leak and therefore should be avoided. Sedation of infants with fluctuating cerebral blood flow velocity theoretically decreases the risk of IVH. (See also Chapter 76.)

Although the survival of infants with RDS has improved greatly, the survival with or without respiratory and neurologic sequelae is highly dependent on birth- weight and gestational age. Major morbidity (BPD/CLD, NEC, and severe IVH) and poor postnatal growth remain high for the smallest infants.