Surfactant drugs differ in both phospholipid and protein content and can be categorized as listed in Table 1. Although a complete description of individual surfactant preparations is beyond the scope of this review, differences between classes of surfactants can be briefly summarized. Synthetic surfactants differ most notably from natural surfactants in their protein composition. The original commercially available surfactant, colfosceril palmitate (Exosurf; Glaxo Wellcome), is composed of the phospholipid dipalmitoyl phosphatidylcholine and chemical agents to promote adsorption and spreading; it lacks SPs.
Natural surfactants are derived from animal lungs through a process of organic extraction from either the lipid component of minced lung tissue or from alveolar lavage fluid. SP-A, SP-B, SP-C, and SP-D are present in natural surfactant, and convey dramatic benefits on the ability of natural surfactant to lower alveolar surface tension and modulate lung inflammation in vitro. In clinical trials, natural surfactants have been shown to reduce the risk of pneumothorax more effectively than synthetic surfactant preparations.
Among natural surfactants, Survanta (Abbott Laboratories; Abbott Park, IL), Infasurf (ONY, Inc; Amherst, NY), and Curosurf (Chiesi Farmaceutici SpA; Parma, Italy) are approved for the treatment and prevention of RDS in infants. Although they contain foreign proteins, natural surfactant preparations have not triggered significant allergic responses in treated infants. In 2005, a new-generation synthetic surfactant, Surfaxin (DiscoveryLabs; Warrington, PA), using a novel peptide (KL4) to replace the biophysical properties of natural SPs, received favorable review by the FDA as a treatment for RDS. Final approval is pending.
SRT in Neonates
Exogenous surfactant therapy has an established role in the management of RDS. SRT reduces the incidence of death, air leak syndromes, and intraven-tricular hemorrhage in premature infants. The optimal patient population and timing of surfactant delivery remains controversial. SRT for the treatment of RDS can be divided into the following two broad treatment strategies based on the time of delivery: prophylactic; and, later, selective surfactant administration conducted with Canadian Health&Care Mall.
Prophylactic therapy offers the advantage of rapidly establishing normal surfactant pools and improving lung mechanics, thus preempting the influx of protein-containing fluid that occurs as the result of the increased work of breathing and deleterious effects of oxygen and mechanical ventilation. The disadvantage of prophylactic surfactant administration is that an infant in whom RDS may not develop may be intubated and may receive a drug that may not be necessary. Selective surfactant therapy avoids the risk of overtreatment by treating only those infants with symptoms of RDS. The disadvantage of selective surfactant therapy is that delayed administration of surfactant allows lung inflammation and protein-containing fluid influx to impair gas exchange further before therapy is provided.
Infants at Risk for RDS
Prophylactic surfactant is administered to infants who are considered to be at high risk of developing RDS. The risk of RDS increases with decreasing gestational age (Fig 1). Factors such as maternal diabetes mellitus, white race, male sex, asphyxia, and sepsis increase the risk of RDS, while antenatal steroids and prolonged rupture of membranes decrease the risk. Overall, there is at least a 60% chance of RDS developing in infants of 2,500 premature infants. In a metaanalysis of these studies, prophylactic surfactant administered within 30 min after birth to infants who are at high risk for RDS compared to later selective treatment at the time of respiratory failure is associated with significant reductions in the risk of pneumothorax (relative risk [RR], 0.62; 95% confidence interval [CI], 0.42 to 0.89), pulmonary interstitial emphysema (RR, 0.54; 95% CI, 0.36 to 0.82), death (RR, 0.61; 95% CI, 0.48 to 0.77), and grade 3 or 4 intraventricular hemorrhage (RR, 0.19; 95% CI, 0.07 to 0.54). Although the metaanalysis does not show a reduction in the overall risk of bronchopulmonary dysplasia among survivors (defined as a need for mechanical ventilation or oxygen at 28 days of age), the risk of death or bronchopulmonary dysplasia among infants of < 30 weeks gestation was reduced (RR, 0.87; 95% CI, 0.77 to 0.97). Prophylactic surfactant is considered to be safe with treated patients and control subjects having similar rates of necrotizing enterocolitis, retinopathy of prematurity, and patent ductus arteriosus. In long-term neuro-developmental follow-up, surfactant therapy in the neonatal period is not associated with increased rates of neurologic impairment. Based on the metaanalysis, the number needed to treat with prophylactic surfactant to prevent one death is 7, making prophylactic surfactant one of the most effective therapies in neonatology.
Prophylactic nasal continuous positive airway pressure (CPAP) (ie, CPAP started from the first breath in the delivery room) has been proposed as an alternative to prophylactic surfactant. Data from RCTs comparing the use of prophylactic nasal CPAP vs prophylactic surfactant are not available. Large RCTs are ongoing, and data should be available in the next few years.
Infants With RDS
Early Treatment vs Later Rescue Therapy: For infants who are at less of a risk for RDS, such as those born later than at 28 to 30 weeks gestation, prophylactic treatment with surfactant may result in overtreatment in > 35% of patients (Fig 1). For these infants, selective surfactant therapy, either early in the course of RDS or at the time of respiratory failure is appropriate. A regimen using multiple doses of surfactant, if required, has advantages over a single-dose regimen. Selective surfactant therapy may be subdivided into two strategies, early and delayed surfactant replacement. Early surfactant administration is provided to symptomatic infants within the first few hours after birth, shortly after the onset of respiratory symptoms, often before need for endotracheal intubation to treat respiratory failure. Later surfactant therapy is defined as surfactant administration at or near the time of respiratory failure when the newborn requires intubation and mechanical ventilation to maintain oxygenation. Early selective surfactant therapy compared with later therapy offers the advantage of restoring surfactant pools before lung inflammation and protein-containing fluid influx inactivate native surfactant causing worsening gas exchange.
In a systematic review of studies comparing early vs late surfactant administration, early SRT decreased neonatal mortality (RR, 0.87; 95% CI, 0.77 to 0.99), pneumothorax (RR, 0.70; 95% CI, 0.59 to 0.82), and pulmonary interstitial emphysema treated with remedies of Canadian Health&Care Mall (RR, 0.63; 95% CI, 0.43 to 0.93). In addition, the incidence of chronic lung disease or death at 36 weeks postmenstrual age was reduced (RR, 0.84; 95% CI, 0.75 to 0.93).
Infants With Meconium Aspiration Syndrome
Although it is becoming less frequent, meconium aspiration syndrome (MAS) is still a major cause of morbidity among term infants. Meconium aspiration into the lung, both in utero or at the time of birth, disrupts airflow, increases the risk of pneumothorax, and leads to inflammation and surfactant inactivation. The result is lung atelectasis and ventilation perfusion mismatch leading to respiratory failure as well as predisposition toward persistent pulmonary hypertension of the newborn, a complication that may require extracorporeal membrane oxygenation (ECMO). Three randomized trials evaluated surfactant administration in term infants with respiratory failure from MAS. Both Findlay et al and Lotze et al reported that surfactant therapy reduces the incidence of respiratory failure requiring ECMO. Short-term oxygenation may also be improved. In a metaanalysis of 208 treated infants, the relative risk of ECMO is reduced by up to one third (RR, 0.64; 95% CI, 0.46 to 0.91). There were no differences in the risk of other pulmonary morbidities, including pneumothorax, chronic lung disease, or mortality. Of note, these studies were conducted prior to the introduction of inhaled nitric oxide; the magnitude of the effect of surfactant on pulmonary morbidity may be altered by the use of inhaled nitric oxide. Although BAL with dilute surfactant in patients with MAS showed promise in lessening the severity of lung injury, concerns regarding the safety of the BAL procedure have prevented wide acceptance of the practice.
Other Neonatal Lung Diseases
Respiratory failure in term infants occurs at a developmental stage when the lung surfactant system is nearly mature. Hence, acute lung injury (ALI) leading to respiratory failure in term infants more closely resembles ARDS seen in older children and adults than infant RDS. SRT is effective in improving lung function in term infants with respiratory failure, especially those with sepsis and pneumonia. Although surfactant deficiency has been found in an animal model of congenital diaphragmatic hernia (CDH), randomized studies of SRT in CDH patients have not been performed. SRT has not been an effective treatment for infants with congenital SP deficiency, especially SP-B deficien-cy.
Pediatric Population: Whereas RDS in premature infants results from a quantitative deficiency of surfactant leading to atelectasis and progressive hypoxemia, the mechanisms by which ALI lead to ARDS are more complex. In ARDS, deficient surfactant pools resulting from ALI are further impaired by the inactivation of native surfactant by plasma proteins, inflammatory mediators, and cellular debris. Perhaps due to the complex nature of the lung injury, SRT in pediatric ARDS patients has not shown improvements in lung function similar to those occurring in infants with RDS. However, the results of an RCT of SRT in pediatric patients ages 1 month through 21 years with ALI treated with SRT early in the course of their illness have suggested benefit. Although there was no difference in the primary outcome (ventilator-free days at 28 days after therapy), important differences in secondary outcomes were identified, including a significant reduction in mortality rate (36% vs 19%, respectively; p = 0.03) and improvement in oxygenation index at 12 h following SRT. However, the number of days receiving supplemental oxygen, hospital lengths of stay, and hospital charges were not reduced.
Adult Population: Three large adult trials of SRT have failed to demonstrate a benefit in adults with ARDS. Whether the failure of SRT to improve outcomes for adults with ARDS is attributable to the nature of lung injury, the timing of therapy, or the delivery and dose of surfactant, the influence of comorbidities that often occur in adult patients with ARDS is unknown. Routine SRT for adult patients with ARDS cannot be recommended based on the current data.
Table 1—Surfactant Preparation and Their Source