Which condition in a preterm infant in the neonatal period can increase the risk for respiratory distress?

Epidemiology

Respiratory distress syndrome (RDS) is primarily a disease of premature infants. Approximately 70-80% of low birth weight infants below 1000 grams develop respiratory signs and symptoms requiring therapy. The incidence of RDS is decreased towards term gestation. Male infants are generally at higher risk for the condition than females. The risk of RDS is decreased by administration of prenatal glucocorticoids to the mother Porto et al (2011). Surfactant therapy reduces the risk of RDS when used prophylactically at birth. Also, there is a decreased morbidity and mortality when surfactant is administered as rescue or treatment after the development of signs and symptoms of RDS, Kendig et al (1998), Kattwinkel et al (2000), Soll and Blanco (2001), Sandri et al (2010), Polin et al (2014).

Respiratory Distress Syndrome

RDS, also known as hyaline membrane disease, is an acute pulmonary process that is common in premature neonates. The disorder is characterized by hyaline membrane formation and fibrin deposition in diffuse areas of atelectasis. Although severe RDS is associated with increased thrombin generation and decreased levels of AT, interventions aimed at addressing these abnormalities have yielded inconclusive results. Plasmin or plasminogen may enhance survival; heparin is of uncertain benefit, and AT supplementation may increase mortality. Additional studies are needed to explore the utility of anticoagulant or thrombolytic therapies in RDS. A laboratory profile consistent with mild DIC is common in RDS; fibrinogen levels are decreased, and levels of D-dimer are elevated. An unexpected increase in ventilatory support should raise the suspicion of pulmonary embolism in this population.

Epidemiology of Respiratory Distress Syndrome

RDS is closely associated with preterm birth, with the incidence increasing as gestational age decreases. The standard diagnosis for RDS requires progressive respiratory failure beginning at or shortly after birth. The respiratory failure is characterized by respiratory distress as clinically identified by tachypnea, grunting, nasal flaring, and chest wall retractions and an increasing oxygen requirement. The chest film shows poor inflation with a uniform hazy and granular appearance with air bronchograms. The odds ratio for RDS at 34 weeks' gestational age is 40 relative to term infants (Figure 158-2, A).10 The risk is much higher and approaches 100% at gestations below 34 weeks (Figure 158-2, B).11 The prediction of RDS with the lecithin/sphingomyelin (L/S) ratio also is shown for normal pregnancies in the figure relative to gestational age.12 The human lung is not consistently mature enough to avoid RDS until a gestational age of about 35 weeks, but in clinical practice the incidence of RDS at 35 weeks is still about 20%. This discrepancy is explained by the human lung's remarkable capacity to induce lung maturation from abnormalities associated with preterm birth or in response to antenatal corticosteroid treatments.

This epidemiology and the diagnosis of RDS can be confounded by a number of factors frequently encountered in neonatal practice. Low-birth-weight infants at high risk of RDS often are intubated in the delivery room and treated with surfactant, which prevents a diagnosis of surfactant-deficiency RDS. The management strategy of initiating CPAP therapy in the delivery room to assist newborn transition can mitigate the early respiratory distress and the need for oxygen.13,14 Further, for epidemiologic purposes, the NICHD Neonatal Research Network (NRN) has simplified the clinical diagnosis of RDS. For the interval 1997 to 2002, the NRN diagnosis of RDS required oxygen use for the interval of 6 to 24 hours after birth with some respiratory support to 24 hours and a chest film consistent with RDS.15 In that era, the incidence of RDS was 63% for infants weighing 500 to 1000 g. In contrast for the years 2003 to 2007, the diagnosis of RDS was given to 95% of 22 to 28 weeks' gestational age infants based only on the need for oxygen for more than the first 6 hours of life.16 In contrast, 69% of 309 patients with birth weights of 0.5 to 1 kg were successfully managed with CPAP and without surfactant in South Africa.17 The delivery room management of the very preterm infant with CPAP likely can decrease the frequency of the diagnosis of RDS. In contrast, intubation and ventilation in the delivery room are likely to result in a diagnosis of RDS even if the infant has relatively clear lungs and no oxygen requirement. Further, the smallest and most immature infants may need CPAP to maintain functional residual capacity (FRC) and to decrease apnea.18 These infants may be given a diagnosis of RDS even if surfactant is adequate.

RDS is a diagnosis of exclusion, particularly in the very preterm infant (Box 158-1). Very preterm infants are born because the pregnancy is not normal. A frequent cause of very preterm birth is preeclampsia, which can result in fetal growth restriction and abnormal lung parenchymal and microvascular development in animal models and in infants.19 The associated respiratory abnormalities may coexist or mimic RDS. Severe pulmonary hypoplasia is a distinct diagnosis resulting from space-occupying masses in the chest, which inhibit fetal breathing, or a lack of amniotic fluid (Potter syndrome, prolonged rupture of membranes). However, milder variants of pulmonary hypoplasia are probably frequent and difficult to distinguish from RDS. The majority of preterm infants born at <30 weeks' gestational age will have been exposed to histologic chorioamnionitis,20 and the inflammation in amniotic fluid results in inflammation in the fetal lungs even if frank pneumonia or positive cultures are not identified.21 Tracheal aspirates of these infants contain inflammatory cells and increased levels of cytokines. The organisms are often low-grade pathogens such as Ureaplasma that do not grow using standard microbiologic techniques (see Chapter 79).

Proinflammatory mediators such as lipopolysaccharide, interleukin-1, or live organisms cause an inhibition of alveolar development and microvascular injury in the preterm fetal lung.22 Similarly, antenatal corticosteroids inhibit saccular and alveolar development in multiple animal models.23 In fetal sheep some inflammatory stimuli and antenatal corticosteroids increase surfactant and thus mature the fetal lungs.24 However, the adverse effects of inflammation and interference with lung structural development may contribute to the variable presentations and progression of RDS. Some infants will have frank pneumonia at birth from pathogens such as Group B streptococcus and Escherichia coli with clinical presentations that mimic severe RDS.

The incidence of the diagnosis of transient tachypnea of the newborn increases as gestational age decreases (see Figure 158-2, A). Transient tachypnea is respiratory distress resulting from delayed clearance of fetal lung fluid from the airways and lung parenchyma. This abnormality is diagnosed primarily in moderately preterm infants or term infants delivered by cesarean section before labor.25 However, the sodium transporters that help keep the air space free of excess fluid following delivery are developmentally regulated, and low function in the preterm lung likely contributes to RDS.26 Gastric aspirates from infants with a diagnosis of transient tachypnea also have decreased lamellar body counts and surfactant function.27 Therefore, RDS likely includes the pathophysiology of delayed fluid clearance and may be indistinguishable from severe transient tachypnea.

RDS is in part a diagnosis of exclusion because the clinician relies only on clinical and radiologic findings. Any cause of respiratory compromise will result in tachypnea, retractions, and flaring in the term and preterm infant. The hazy lungs by radiologic assessment can reflect surfactant deficiency, pneumonia, hypoplasia, or excess fluid, or simply the lungs at expiration in the early hours of life. Although not widely used, a more specific diagnosis can result from analyses of gastric fluid aspirated soon after birth by counting lamellar bodies or measuring the stability of bubbles.28,29 For infants thought to have RDS, perhaps the best diagnostic test is the clinical response to surfactant treatment characterized primarily by an acute increase in oxygenation. Infants can have RDS and other lung abnormalities at the same time. For example, fetuses exposed to chorioamnionitis and funisitis—an indicator of a fetal inflammatory response—will have decreased clinical response to surfactant treatment.30

F. Respiratory Distress Syndrome

Respiratory distress syndrome (RDS), or respiratory insufficiency of prematurity, is one of the major complications seen in premature, low birth-weight (LBW) infants. The incidence of RDS in premature infants between 500 and 1500 g ranges from 50 to 80%. Infants with lower birthweights and gestational ages have a higher incidence of RDS. The relative risk for developing RDS and its complications is 1:7 for male premature infants compared to female infants [74].

Antenatal steroid administration to women in premature labor has been shown to induce fetal lung maturation and decrease the incidence and severity of RDS in the premature newborn. Usually, either bethamethasone or dexamethasone is administered within 24 hours of delivery to women who are in premature labor at less than 32 weeks gestation. Administering antenatal steroids was found to be more effective in preventing or ameliorating RDS in the female premature infant than in the male. After steroid administration, the incidence of RDS in the male was 29.1% and in the female 8.6%. The pharmacologic and physiologic response to antenatal steroids may be related to the presence of an endogenous inhibitor of surfactant production in the lung. Dehydrotestosterone has been shown to inhibit fetal pulmonary surfactant production. In addition, a lag in surfactant production has been demonstrated in the male rabbit fetus. An increase in the incidence of RDS has been described in male twin pairs compared to female twin pairs, and the male twins showed the same blunted response to antenatal administration of betamethasone. Even though the male fetus is usually heavier than the female twin, he is at a greater risk for RDS [74–78].

Surfactant production or the maturity of the fetal lung can be evaluated by measuring the L/S ratio (lecithin/sphingomyelin) in the amniotic fluid. The L/S ratio for white male fetuses is the lowest (most immature) when compared with white female, black female, and black male fetuses. These data suggest a relative delay in surfactant production, which may be genetically inherent in white males. It may be that the response of the fetal lung to various hormones such as glucocorticoids and androgens is influenced by genetic factors that control development [53].

Chronic lung disease (CLD) is a complication seen in small premature infants in association with RDS and its treatment modalities (especially mechanical ventilation and supplemental oxygen), and with other complications of prematurity including infection and the presence of a patent ductus arteriosus (PDA). The likelihood of developing CLD is inversely related to gestational age and birth weight, and directly related to length of ventilatory therapy. Male gender is also a risk factor for developing CLD. This is consistent with the increased incidence and severity of RDS in male infants. Male preterm infants are also more likely to experience episodes of apnea and bradycardia and to develop such complications as anemia and electrolyte disturbances during the neonatal period [79].

Respiratory Distress Syndrome

Respiratory distress syndrome (RDS), or respiratory insufficiency of prematurity, is one of the major complications seen in premature low birthweight infants. The incidence of RDS in premature infants between 500–1500 g ranges from 50 to 80%. Infants with lower birthweights and gestational ages have a higher incidence of RDS. The relative risk for developing RDS and its complications is 1.7 for male premature infants compared to female infants of the same gestational age. Gender differences in specific measures of airway function have been demonstrated.118–120

Antenatal steroid administration to women in premature labor has been shown to induce fetal lung maturation and decrease the incidence and severity of RDS in the premature newborn. Usually, either bethamethasone or dexamethasone is administered within 24 hours of delivery to women who are in premature labor at less than 32 weeks gestation. The administration of antenatal steroids was found to be more effective in preventing or ameliorating RDS in the female premature infant than in the male. After steroid administration, the incidence of RDS in the male was 29.1% and in the female 8.6%. In premature sheep, pulmonary function measured by compliance, conductance, lung volume and PaO2 showed greater improvement in females than in males after antenatal steroid administration. The pharmacologic and physiologic response to antenatal steroids may be related to the presence of an endogenous inhibitor of surfactant production in the lung in the male infant. Dehydrotestosterone has been shown to inhibit fetal pulmonary surfactant production. A lag in the production of surfactant has been demonstrated in the male rabbit fetus. An increase in the incidence of RDS has been described in preterm male twin pairs compared to preterm female twin pairs; male twins, although heavier, showed the same blunted response to antenatal administration of betamethasone. An increased incidence of RDS also has been noted in girls of unlike-sex preterm twins compared to girl-girl twins. A transchorionic paracrine effect on the female twin has been proposed to account for this observation.58,118,119,121–125

Surfactant production, reflecting the maturity of the fetal lung, can be evaluated by measuring the L/S (lecithin/sphingomyelin) ratio in amniotic fluid. The L/S ratio for white male fetuses is the lowest (most immature) when compared with white female, black female or black male fetuses. The data suggest a relative delay in surfactant production, which may be genetically determined in white males. The response of the fetal lung to various hormones such as glucocorticoids and androgens may be influenced by genetic factors controlling development.83

Chronic lung disease (CLD) is a complication seen in small premature infants in association with RDS and its treatment modalities (especially mechanical ventilation and supplemental oxygen) and with other complications of prematurity including infection and the presence of a patent ductus arteriosus (PDA). The incidence of CLD varies with gestational age, birthweight, and length of ventilatory therapy. Male gender is also a risk factor for the development of CLD. This is consistent with the increased incidence and severity of RDS in male infants. Male preterm infants also are more likely to experience episodes of apnea and bradycardia and to develop anemia and electrolyte disturbances during the neonatal period. Interestingly, a prospective cohort study from Holland of prematurely born infants with and without CLD found a higher prevalence of asthma and respiratory symptoms in young adult women compared to men.126,127

Fetal lung maturity testing

RDS is the most common morbidity associated with prematurity. RDS occurs with incomplete fetal lung development. The incidence of RDS is increased with decreased gestational age at birth. The fetal pulmonary system is one of the last to completely develop, and risk for RDS is inversely correlated with gestational age at delivery. The final stage of fetal lung development, the alveolar stage, involves production of increasing amounts of pulmonary surfactant. In a normal airway, surfactant coats the alveolar epithelial surfaces. It decreases surface tension of the alveolar wall to prevent lung collapse during exhalation. Surfactant deficiency in RDS patients causes both lung collapse and hyperextension of alveoli, leading to fibrosis and hyaline membrane disease. The alveoli in an RDS lung are perfused, but unventilated, resulting in hypoxia, hypercapnia, and respiratory acidosis.

Pulmonary surfactant synthesis by type II pneumocytes in the fetal lung begins at ~28 weeks of gestation. In type II cells, surfactant is packaged and stored in lamellar bodies (LBs). These platelet-sized vesicles made up of phospholipids (PLs; 90%) and surfactant (10%) are exocytosed to the pulmonary airway, where they coat the epithelium. During lung maturation, the PLs in LB change. Analysis of the change in PL content in AF is used to assess lung maturity.

Prevention of RDS is accomplished by preventing PTB or stimulating surfactant production with antenatal corticosteroids. Assessment of FLM status through one of several AF-based tests may assist in making clinical decisions in women with symptoms of preterm labor and/or women, whose labor is induced prior to 39 weeks of gestation. In recent guidelines, ACOG recommended against any elective induction of labor before 39 weeks of gestation; therefore FLM testing is only necessary in emergent situations (i.e., premature rupture of membranes, severe early preeclampsia requiring delivery of an infant, or HDFN). FLM tests help determine whether an NICU is needed when PTB is required. Despite this, numerous outcome studies have failed to demonstrate improvement in neonatal outcomes when FLM information is known. Furthermore, the advent of intratracheal surfactant therapy has improved outcomes for infants with immature lungs. Improved treatment options and reduced clinical utility of the testing have led to a significant decline in available FLM testing methodologies and FLM testing volumes.

Etiology

RDS is primarily a developmental deficiency in the amount of surface-active material at the air-liquid interface of the lung, as demonstrated by pressure-volume curves with air and saline in infants who died from RDS (Avery and Fletcher, 1974). Saline extracts of minced lung from infants who died from RDS have higher surface tensions than those in lungs of controls (Avery and Mead, 1959); this finding is associated with lower levels of total tissue phospholipid (Brumley et al, 1967) and SP-C (Adams et al, 1970). Although on the basis of theoretical considerations of the amount required, a more than adequate amount of phospholipid evidently is present in total lung (Clements and Tooley, 1977), only a small proportion of lung phospholipid is surface-active material (Rieutort et al, 1986).

Infants with RDS may synthesize adequate amounts of SP-C but cannot package and export it to the alveolar surface in a way that makes it function as surfactant. In infants who die, deMello and colleagues (1987) have demonstrated the complete absence of tubular myelin and a modest deficiency of lamellar bodies in type II cells, in comparison with controls. For further discussion of the role of surfactant proteins in RDS, see Chapter 42 on lung development and Chapter 46 on surfactant.

It has been suggested that surfactant function in infants with RDS is inhibited by plasma proteins (Ikegami et al, 1986), which leak into the respiratory bronchioles at the sites of overdistention and epithelial damage. In particular, a plasma protein of relative molecular weight 110,000 has been implicated. Fibrinogen, hemoglobin, and albumin are potent inhibitors of surfactant (Seeger et al, 1993). It is of critical importance for the lungs to have adequate surfactant at the gas-liquid interface from the earliest possible moment after birth; otherwise, acute lung injury and surfactant inhibition will supervene rapidly, contributing to a cycle of worsening disease (Nilsson et al, 1978). Thus, RDS is due to a developmental deficiency of surfactant at birth, but associated lung injury results in surfactant dysfunction as well.

Based on the results of animal experiments, it is estimated that the air spaces of the newborn infant at term contain about 75 mg/kg of SP-C; this compares with only 10 to 15 mg/kg in adults and only 1 to 10 mg/kg in premature infants with RDS (Ikegami et al, 1993). Aside from lower surfactant content, the surfactant from premature infants has decreased biophysical function and is more susceptible to inactivation than surfactant from adults, presumably because it contains lower amounts of surfactant proteins (Ueda et al, 1994). The pool size of alveolar surfactant in recovering premature infants has not been determined but has been measured in preterm monkeys recovering from RDS, in which the pool size increased to 100 mg/kg within 3 to 4 days of birth (Jackson et al, 1986). Dipalmitoyl phosphatidylcholine (DPPC) concentrations in tracheal aspirate samples increase in premature infants recovering from RDS (Hallman et al, 1976). These findings indicate that as premature infants recover from RDS, the alveolar pool size approaches that in the term infant. The evidence suggests that newborn infants need more surfactant than that required in adults for adequate function, which may mean that in the neonatal lung, more surfactant is present in an inactive or catabolic form and that more surfactant is inhibited by excessive fluid and protein. (See also Chapter 46 on surfactant.)

Respiratory Distress Syndrome and Bronchopulmonary Dysplasia

Respiratory distress syndrome (RDS) results from a deficiency in pulmonary surfactant, leading to decreased lung compliance, alveolar instability, progressive atelectasis, and intrapulmonary shunting. The incidence of RDS correlates inversely with gestational age and is increased by male gender, white race, perinatal asphyxia, sepsis, and maternal diabetes mellitus. The incidence of RDS decreases with antenatal steroid administration and prolonged rupture of fetal membranes. Clinically, the newborn presents shortly after birth with hypoxemia, cyanosis, respiratory distress, and progressive respiratory failure. Shunting through the PDA or patent foramen ovale (PFO) may worsen the hypoxemia. Respiratory acidosis develops from respiratory insufficiency, and metabolic acidosis may appear subsequent to circulatory failure. The level of respiratory support, from warm humidified oxygen or continuous positive airway pressure (CPAP) to intubation and ventilation, depends on the respiratory drive and severity of the RDS.

Briefly, the fraction of inspired oxygen (Fio2) is adjusted to maintain partial arterial oxygen tension (Pao2) between 50 and 80 mm Hg (functional oxygen saturation [Spo2] less than 96%). Endotracheal intubation is the safest method of airway control. The goals of ventilation are to provide gas exchange while minimizing volutrauma and barotrauma. The analysis of neonatal data comparing pressure-limited ventilation versus volume-targeted ventilation suggests that volume target ventilation reduces duration of ventilation, pneumothorax, and the rate of severe intraventricular hemorrhage (IVH) (grades 3 or 4).75 The complications of RDS treatment such as pneumothorax, oxygen toxicity, pulmonary interstitial emphysema, subglottic stenosis, and chronic lung disease, needs to be taken into account perioperatively and discussed with the family.

Bronchopulmonary dysplasia (BPD) is defined as the continued need for respiratory support with supplemental oxygen or mechanical ventilation beyond 36 weeks postconception. In addition to RDS, a variety of factors are associated with BPD, including oxygen toxicity, inflammatory mediators, and mechanical ventilation. Other clinical features include inspiratory rales and evidence of increased work of breathing. Hypoxemia is a manifestation of nonhomogenous lung ventilation, intrapulmonary shunt, pulmonary hypertension, and bronchospasm (see Chapter 23). Preoperative evaluation is focused on the clinical condition, especially the degree of respiratory support and medications needed to maintain oxygenation and ventilation. The risks of respiratory complications under anesthesia (such as pneumothorax, bronchospasm, pulmonary hypertension, hypoxia, emergence, and extubation) present significant management challenges.