Respiratory Distress Syndrome

Background: Respiratory distress syndrome (RDS), also known as hyaline membrane disease (HMD), occurs almost exclusively in premature infants. The incidence and severity of RDS are related inversely to the gestational age of the infant. The outcome of RDS has improved in recent years with the increased use of antenatal steroids to improve pulmonary maturity, early postnatal surfactant therapy to replace surfactant deficiency, and gentler techniques of ventilation to minimize damage to the immature lungs. These therapies also have resulted in the survival of premature infants who are smaller and more ill. Although reduced, the incidence and severity of complications of RDS continue to present significant morbidities.

The sequelae of RDS include intracranial hemorrhage and/or periventricular leukomalacia with associated neurodevelopmental delay, septicemia, bronchopulmonary dysplasia (BPD), patent ductus arteriosus (PDA), and pulmonary hemorrhage. Direct attention to anticipating and minimizing these complications and also toward preventing premature delivery whenever possible are strategic goals.

Pathophysiology: A relative deficiency of surfactant, which leads to decrease in lung compliance and functional residual capacity with increased dead space, causes RDS. The resulting large ventilation-perfusion mismatch and right-to-left shunt may involve as much as 80% of cardiac output. Macroscopically, the lungs appear airless and ruddy (ie, liverlike). Thus, the lungs of these infants require a higher critical opening pressure to inflate. Diffuse atelectasis of distal airspaces along with distension of some distal airways and perilymphatic areas are observed microscopically. With progressive atelectasis along with barotrauma or volutrauma and oxygen toxicity, endothelial and epithelial cells lining these distal airways are damaged, resulting in exudation of fibrinous matrix derived from blood.

Hyaline membranes that line the alveoli are formed within one half hour after birth. At 36-72 hours after birth, the epithelium begins to heal and surfactant synthesis begins. The healing process is complex; in infants who are extremely immature and critically ill and in infants born to mothers with chorioamnionitis, a chronic process often ensues, resulting in BPD.

Surfactant is a complex lipoprotein comprised of 6 phospholipids and 4 apoproteins. Functionally, dipalmitoyl phosphatidylcholine (DPPC), or lecithin, is the principle phospholipid. DPPC along with apoproteins SP-B and SP-C or with the addition of other substances (eg, nonionic detergent tyloxapol, C16:0 alcohol hexadecanol [Exosurf]) facilitates adsorption and spreading of DPPC as a monolayer, which lowers the surface tension at the alveolar air-fluid interface in vivo.

The components of pulmonary surfactant are synthesized in the Golgi apparatus of the endoplasmic reticulum of the type II alveolar cell. The components are packaged in multilamellar vesicles in the cytoplasm of the type II alveolar cell and are secreted by a process of exocytosis, the daily rate of which may exceed the weight of the cell. Once secreted, the vesicles unwind to form bipolar monolayers of phospholipid molecules that are dependent on the apoproteins SP-B and SP-C to configure properly in the alveolus. The lipid molecules are enriched in dipalmitoyl acyl groups attached to a glycerol backbone that pack tightly and generate low surface pressures.

Tubular myelin stores surfactant and may depend on SP-B. Corners of the myelin lattice appear to be glued together with the larger apoprotein SP-A, which also may have an important role in phagocytosis. Hypoxia, acidosis, hypothermia, and hypotension may impair surfactant production and/or secretion of surfactant.

In the US : While the greatest risk factor for developing RDS is prematurity, maternal diabetes and asphyxia also are risk factors. All premature infants do not develop RDS. Approximately one half of infants born at 28-32 weeks' gestation develop RDS.

In the US , RDS occurs in approximately 40,000 infants each year and in 14% of low birth weight infants. Incidence of RDS increases with decreasing gestational age and may occur in as many as 45-80% of infants born when younger than 28 weeks' gestation.

Internationally: RDS has been reported in all races worldwide, occurring more often in premature infants of Caucasian ancestry.

Prenatal prevention and prediction of RDS: Obstetricians with experience in fetal medicine should care for mothers whose infants are at an increased risk for developing RDS, preferably at a tertiary perinatal center. Strategies to prevent premature birth (eg, bed rest, tocolytics, appropriate antibiotics) and the prudent use of antenatal steroids to mature fetal lungs may decrease the incidence and severity of RDS. Fetal lung maturity can be predicted by estimating the lecithin-to-sphingomyelin ratio and the presence of phosphatidylglycerol in the amniotic fluid obtained via amniocentesis.
Delivery and resuscitation: A neonatologist experienced in the resuscitation and care of premature infants should attend deliveries of fetuses when younger than 28 weeks' gestation. They are at a high risk of maladaptation, which further inhibits surfactant production.
Surfactant replacement therapy: Mortality of RDS has decreased 50% during the last decade with the advent of surfactant therapy.

Infants diagnosed with RDS who require assisted ventilation with more than 0.40 fraction of inspiratory oxygen (FIO 2 ) should receive intratracheal surfactant as soon as possible, preferably within 2 hours after birth.
Because surfactant is protective of delicate lungs, several investigators have recommended prophylactic use following resuscitation in extremely premature infants (<27 weeks' gestation). However, prophylactic surfactant is expensive and unnecessary in most instances because 40-60% of premature infants do not have surfactant deficiency and, thus, are intubated with its inherent risks.
Premature infants with surfactant deficiency and RDS have an alveolar pool size of approximately 5 mg/kg. Full-term animal models have pool sizes with a range of 50-100 mg/kg. The recommended dose of the clinically available surfactant preparations has a range of 50-200 mg/kg, which is an approximation of the surfactant pool of term newborn lungs. Rapid bolus administration of surfactant after adequate lung recruitment using 2- 4 cm positive end-expiratory pressure (PEEP) and adequate positive pressure may lead to its more homogenous distribution. Most infants require 2 doses; however, as many as 4 doses at 6- to 12-hour intervals have been used in several clinical trials. If the infant improves rapidly after only 1 dose, the infant most likely does not have RDS. Conversely, in infants who respond poorly or are nonresponders to surfactant, exclude PDA, pneumonia, and complications of ventilation (air leak), especially prior to using third and subsequent doses.
Clinical trials with protein-containing natural surfactants result in fewer complications and a more rapid improvement in the infant's respiratory status. The currently marketed natural surfactants have varying amounts of phospholipids (mostly desaturated phosphatidylcholine) and apoprotein B and C but not apoprotein A. Apoprotein A may be important for host defense. In 2 recent reviews, Notter and Kresch et al summarized data from extensive biophysical studies, in vitro and whole animal biochemical studies, molecular and physiologic studies, and several large international clinical trials.

Oxygen and continuous positive airway pressure: In 1971, continuous positive airway pressure (CPAP) was introduced as the primary therapeutic modality when Gregory et al demonstrated a marked reduction in RDS mortality. Oxygen was the primary therapeutic modality prior to the introduction of CPAP.

Oxygen via hood still is used for treating infants with mild RDS.
CPAP keeps the alveoli open at the end of expiration, thereby decreasing the right-to-left pulmonary shunt.
CPAP may be administered via the endotracheal tube, nasal prongs, or nasopharyngeal tubes (in larger infants).
CPAP is an adjunct therapy following surfactant administration, if prolonged assisted ventilation is not required.
CPAP may be used following extubation in individuals with RDS to prevent atelectasis and/or prevent apnea in premature infants.
The goal of therapy for patients with RDS is to maintain a pH of 7.25-7.4, an arterial oxygen (PaO 2 ) of 50- 70 mm Hg, and a carbon dioxide pressure (PCO 2 ) of 40- 65 mm Hg, depending on the infant's clinical status.

Kirby and deLemos introduced assisted ventilation 2 decades ago. Assisted ventilation further decreased RDS-related mortality; however, earlier ventilators were associated with complications, such as air leaks, BPD (secondary to barotrauma or volutrauma), airway damage, and intraventricular hemorrhage. Advances in microprocessor-based technology, transducers, and real-time monitoring have enabled patient-driven ventilator control and synchronization of mechanical ventilation with patient effort. The novelty of the newer ventilation techniques has generated several controversies that remain to be resolved. Among these controversies are signal detection and transduction, optimal volume delivery (ventilation modes), and weaning from mechanical ventilation.
Consider ventilation as a necessary physiologic support while the infant recovers from RDS. Several investigators have suggested that permissive hypercapnia with arterial carbon dioxide (PaCO 2 ) with a range of 45- 55 mm Hg (with adequate lung volume), may facilitate weaning during recovery from RDS. To minimize the complications of conventional intermittent mandatory ventilation, newer ventilation techniques have been introduced, including the following:

Synchronous intermittent mandatory ventilation is a technique wherein some of the patient's respirations are synchronized with breaths delivered by the ventilator. In a recent randomized controlled trial, the incidence of BPD (defined as oxygen requirement at corrected gestational age of 36 wk) was reduced significantly when compared with standard intermittent mandatory ventilation (47% vs 72%; p <0.05).
Assist-control ventilation also has been suggested to improve outcome.
Some physicians use pressure-support ventilation to wean the infants who have developed chronic lung changes.
High-frequency ventilation (HFV) is a technique wherein small tidal volumes (less than anatomic dead space) usually are delivered at rapid frequencies. HFV originally was designed to treat patients with air leak. Numerous studies in animal models of RDS demonstrate that HFV promotes more uniform lung inflation, improves lung mechanics and gas exchange, and reduces exudative alveolar edema, air leak, and lung inflammation. Although animal studies are unequivocal, human data are less clear. Some clinical trials demonstrate that HFV can reduce the occurrence of chronic lung disease, whereas other studies have demonstrated no effect. Adequate clinical trials controlling for techniques of resuscitation, surfactant therapy, and comparing HFV with synchronous intermittent mandatory ventilation are awaited. HFV techniques have a learning curve, and the optimal ventilator strategy varies with the stage of RDS. These ventilators include the following:

High-frequency oscillatory ventilation (10-15 Hz): Because expiration occurs actively, monitor patients for hypocarbia in order to prevent periventricular leukomalacia. Controlled trials of the use of high-frequency oscillatory ventilation (HFOV) in reducing BPD in infants with RDS have been controversial. Perhaps the unfavorable outcome of HFOV in some of these studies can be attributed to (1) having very low incidence of BPD with antenatal steroid use and, therefore, inadequate sample size to detect a difference, (2) not using an optimal lung volume strategy in patients treated with HFOV, (3) definition and differences in chorioamnionitis, or (4) differences in resuscitation techniques at birth.
High-frequency jet ventilation: Its frequency range is 4-11 Hz (usually 7 Hz), but it has to be used in tandem with a conventional ventilator to provide PEEP and sigh breaths. It has been demonstrated to decrease air leaks. Because the solenoid valves open intermittently to provide jet breaths, high-frequency jet ventilation may be preferred by some neonatologists to treat infants with air leaks.
High-frequency flow interrupter: Its frequency range is 6-15 Hz, with the advantages of a built-in conventional ventilator and an ability to provide sigh breaths. Its use also is associated with a decrease in the incidence of air leaks in infants with RDS.

Supportive therapy includes the following:

Temperature regulation: Hypothermia increases oxygen consumption, thereby further compromising infants with RDS who are born prematurely. Therefore, prevent hypothermia in infants with RDS during delivery, resuscitation, and transport. Care for these infants in a neutral thermal environment with the use of a double-walled incubator or radiant warmer.
Fluids, metabolism, and nutrition: In infants with RDS, initially administer 5% or 10% dextrose intravenously at 60-80 mL/kg/d. Closely monitor blood glucose (Dextrostix), electrolytes, calcium, phosphorous, renal function, and hydration (determined by body weight and urine output) to prevent any imbalance. Add calcium at birth to the initial intravenous fluid. Start electrolytes as soon as the infant voids and as indicated by electrolytes. Gradually increase the intake of fluid to 120-140 mL/kg/d. Extremely premature infants occasionally may require fluid intake of as much as 200-300 mL/kg or more because of insensible water loss occurring from their large body surfaces.

Once the infant is stable, add intravenous nutrition with amino acids and lipid. After the respiratory status is stable, initiate a small volume of gastric feeds (preferably breast milk) via a tube to initially stimulate gut development and, thereafter, provide nutrition as intravenous nutritional support is being decreased.

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