Pathophysiology of Respiratory Distress Syndrome

Dosing of Antenatal Corticosteroids

ANS are standard of care at 24 to 37 weeks for women at risk of preterm delivery. However, the standard-of-care treatment is the dosing initially used in 1972 by Liggins and Howie. There has not been an interest in evaluating the treatment, as it is off label and not FDA approved. We have been concerned that the dose is too high and have formally tested lower doses in fetal sheep and rhesus macaque models, together with pharmacokinetic (PK) and pharmacodynamic (PD) studies in reproductive-age, nonpregnant women in India. The concern is to model development of the human fetus for developmental disorders of health and disease (DoHAD)—for very delayed effects on cardiovascular function and metabolic syndrome, as occur in animal models. Fig. 157.3 is a sketch of maternal blood levels for the frequently used treatments. The standard of care in the United States is a 2 to 12 mg dose of a 1:1 mixture of β phosphate + betamethasone acetate (BetaAc). The BetaAc functions as a slow-release reservoir of betamethasone. We tested only the BetaAc form of betamethasone, which is effective for lung maturation in fetal sheep and monkeys, as is the betamethasone phosphate, which yields much higher fetal plasma levels. Therefore, phosphorylated betamethasone or dexamethasone simply exposes the fetus to excess drug. Using infusions of betamethasone phosphate, we determined that fetal exposure of 1 ng/mL was sufficient for lung maturation in sheep or monkeys. A durable response requires greater than 48 hours exposure for lung maturation to have a permanent effect. The exposure needs to be continuous for 48 hours or longer without interruption. ^, Of interest for low- and middle-income countries (LMIC), oral doses of very inexpensive and stable oral drugs are as effective as intramuscular injections. A concern for the drug used routinely in the United States is that betamethasone is measurable in the maternal blood for greater than 14 days, causing prolonged adrenal suppression and fetal exposures. ^, To change standard of care, new lower dosing strategies will need to be tested. Our conclusion is that we have used the wrong dose of the wrong drug for 40 years.

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. ^, 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. 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. 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. 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. 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 157.1 ). 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. The associated respiratory abnormalities may coexist or may 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 less than 30 weeks’ gestational age will have been exposed to histologic chorioamnionitis, and the inflammation in amniotic fluid results in inflammation in the fetal lungs even if frank pneumonia or positive cultures are not identified. 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 can inhibit alveolar development and cause microvascular injury in the preterm fetal lung. Similarly, ANS inhibit saccular and alveolar development in multiple animal models. In fetal sheep some inflammatory stimuli and ANS increase surfactant and thus mature the fetal lungs. 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 Fig. 157.2A ). 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. 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. Gastric aspirates from infants with a diagnosis of transient tachypnea also have decreased lamellar body counts and surfactant function. 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 imaged on 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. ^, 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.

Lung Injury With Mechanical Ventilation

A major factor determining how the preterm lung responds to treatment and injury is the structural maturation of the lung at delivery. The preterm lung with RDS has lung gas pressure-volume characteristics quite distinct from the term or adult lung. As illustrated in Fig. 157.6 , all lung volume variables are less for the preterm infant with RDS than in the adult lung. FRC and total lung capacity (TLC) are lower. Pressures needed to achieve lung opening and TLC are higher for the premature lung. Pressure-volume characteristics resulting from the immature air space structure explain why the preterm lung is more easily injured by mechanical ventilation.

The lungs of infants who have died from RDS are atelectatic with evidence of alveolar and interstitial edema, hyaline membranes, hemorrhage in distal saccules, and distorted small airways. Hyaline membranes are coagula of cell debris, surfactant, and serum proteins caused by epithelial injury, and result in large amounts of soluble and insoluble proteins in the air spaces. The earliest anatomic lesion identified in the lungs of infants who died of RDS shortly after birth is epithelial disruption in the small airways. In preterm surfactant-deficient rabbits, bronchiolar epithelial injury develops within minutes of delivery and ventilation. This injury can be prevented with surfactant treatment ( Fig. 157.7 ). The epithelial damage occurs because the small airways of the immature lung are compliant and distort during ventilation. Lung fluid clearance is not complete, and small airways are fluid-filled at end-expiration. Ventilation requires high peak pressures in the noncompliant lung to achieve relatively normal tidal volumes and carbon dioxide removal.

The preterm lung has both endothelial and epithelial abnormalities that cause proteinaceous pulmonary edema after delivery and ventilation. In preterm lambs ventilated for the first 3 hours of life, 11.5% per hour of the labeled albumin mixed with the fetal lung fluid at birth left the lung, and 1.7% per hour of the labeled albumin given intravascularly at birth was recovered from the air spaces, demonstrating the bidirectional movement of albumin across an injured alveolar epithelium. The protein in the alveolar washes increased more than fourfold, indicating that the net protein movement was from the intravascular compartment to the air spaces. The rate of protein accumulation in the air spaces was striking in preterm ventilated rabbits. Approximately 2% to 3% of the intravascularly injected and labeled albumin was recovered from the air spaces within 20 minutes of birth. The leakage was not homogeneous. Leakage involved an increasing number of saccules with time and appeared to occur directly into the alveoli rather than at the bronchiolar level.

Lung gas volumes of infants with RDS can be low because the lung has not yet developed sufficiently to hold much gas, or because distal air spaces are uninflated (see Fig. 157.6 ). Another cause of the volume loss in the lungs of infants with RDS is alveolar edema. After 3 hours of ventilation, the TLC was 48 mL/kg in preterm monkeys without RDS and 19 mL/kg for monkeys with RDS. The flash-frozen lungs, evaluated by light and scanning electron microscopy, of animals with RDS had overexpanded distal airways and underexpanded and fluid-filled alveolar spaces ( Fig. 157.8 ). By scanning electron microscopy, the alveoli of animals with RDS were filled with proteinaceous liquid, and the interstitium was swollen by edema fluid ( Fig. 157.9 ). The lungs of monkeys with RDS exhibit alveolar and interstitial edema because of the slow clearance of fetal lung fluid after birth and the entrance of proteinaceous edema into the air spaces.

Five clinical variables are important determinants of the amount of edema formation: gestational age, tidal volume, positive end-expiratory pressure (PEEP), antenatal corticosteroid treatment, and surfactant treatment. In preterm animal models, protein leaks from the vascular space to the alveolar space and from the alveolar space to the vascular space increase as gestation decreases ( Fig. 157.10 ). The pressure needed to achieve an adequate tidal volume and gas exchange decreases as gestational age increases. Therefore, a possible explanation of the increased leak is the barotrauma caused by the ventilatory requirements needed to support the more immature lung. In the mature lung, pulmonary edema occurs after lung overdistension using high tidal volumes (volutrauma). High pressures or volumes are not required to injure the immature surfactant-deficient lung because nonuniform inflation causes focal overdistension. Without surfactant treatment, pulmonary edema occurs with relatively low tidal volume ventilation. The end-expiratory volume of the preterm lung also is an important injury variable. Ventilation of preterm lambs with the same tidal volume results in different amounts of protein recovery from the airways, depending on the PEEP used to support end-expiratory lung volume. Antenatal treatment with ANS also can greatly decrease injury and edema. ^,

These observations describe outcomes of preterm animals ventilated from birth for several hours. The preterm lung may be most easily injured with the initiation of ventilation at birth because the air spaces are fluid-filled and the clinician wants to establish gas exchange quickly. Tidal volumes increased to 15 mL/kg severely injure the airways of preterm lambs, and subsequent ventilation amplifies and propagates that injury to the lung parenchyma ( Fig. 157.11 ). ^, The injury can be decreased with lower tidal volumes, the use of PEEP to maintain FRC, and surfactant treatment. These experiments in animal models provide the context for understanding why the gentle recruitment of tidal volume in the delivery room when supported by CPAP can decrease the number of infants diagnosed with RDS.

An integrated perspective on the major variables that determine the pathophysiology of RDS is shown in Fig. 157.12 . Lung development as modified by gestational age and exposures such as ANS, inflammation, and growth restriction determine the lung structure and the amount of surfactant that the preterm infant has at birth. The preterm lung structure can be injured to alter tissue function, primarily by epithelial disruption causing pulmonary edema. An inadequate surfactant pool can be corrected with surfactant treatment. The integration of these variables primarily determines the severity of RDS.