Guidance for the Clinician in Rendering Pediatric Care CLINICAL REPORT Surfactant Replacement Therapy for Preterm and Term Neonates With Respiratory Distress Richard A. Polin, MD, FAAP, Waldemar A. Carlo, MD, FAAP, abstract and COMMITTEE ON FETUS AND NEWBORN Respiratory failure secondary to surfactant deficiency is a major cause KEY WORDS surfactant, antenatal steroids, respiratory distress syndrome, of morbidity and mortality in preterm infants. Surfactant therapy sub- meconium aspiration syndrome, neonatal pneumonia, neonatal stantially reduces mortality and respiratory morbidity for this popu- sepsis, congenital diaphragmatic hernia, pulmonary hemorrhage, lation. Secondary surfactant deficiency also contributes to acute persistent pulmonary hypertension, preterm, term respiratory morbidity in late-preterm and term neonates with meco- ABBREVIATIONS nium aspiration syndrome, pneumonia/sepsis, and perhaps pulmonary BPD—bronchopulmonary dysplasia hemorrhage; surfactant replacement may be beneficial for these in- CI—confidence interval CPAP—continuous positive airway pressure fants. This statement summarizes the evidence regarding indications, ECMO—extracorporeal membrane oxygenation administration, formulations, and outcomes for surfactant-replacement INSURE—intubation, surfactant administration, and extubation therapy. The clinical strategy of intubation, surfactant administra- LOE—level of evidence — fi tion, and extubation to continuous positive airway pressure and NNTB number needed to bene t RDS—respiratory distress syndrome the effect of continuous positive airway pressure on outcomes RR—relative risk and surfactant use in preterm infants are also reviewed. Pediatrics SP-B—surfactant protein B 2014;133:156–163 This document is copyrighted and is property of the American Academy of Pediatrics and its Board of Directors. All authors have filed conflict of interest statements with the American Academy of Pediatrics. Any conflicts have been resolved through INTRODUCTION a process approved by the Board of Directors. The American Academy of Pediatrics has neither solicited nor accepted any Surfactant replacement was established as an effective and safe commercial involvement in the development of the content of therapy for immaturity-related surfactant deficiency by the early this publication. 1990s.1 Systematic reviews of randomized, controlled trials confirmed The guidance in this report does not indicate an exclusive that surfactant administration in preterm infants with established course of treatment or serve as a standard of medical care. Variations, taking into account individual circumstances, may be respiratory distress syndrome (RDS) reduces mortality, decreases the appropriate. incidence of pulmonary air leak (pneumothoraces and pulmonary interstitial emphysema), and lowers the risk of chronic lung disease or death at 28 days of age (Table 1).2–11 Subsequent trials indicated that prophylactic or early administration of surfactant resulted in fewer pneumothoraces, less pulmonary interstitial emphysema, and improved survival without bronchopulmonary dysplasia (BPD). How- ever, recent randomized clinical trials indicate that the benefits of prophylactic surfactant are no longer evident in groups of infants when continuous positive airway pressure (CPAP) is used routinely.5 This clinical report updates a 2008 report from the American Academy of www.pediatrics.org/cgi/doi/10.1542/peds.2013-3443 Pediatrics.1 As in the previous report, a number of clinically important doi:10.1542/peds.2013-3443 topics are reviewed surrounding use of surfactant, including pro- All clinical reports from the American Academy of Pediatrics phylactic versus rescue replacement, preparations and administration automatically expire 5 years after publication unless reaffirmed, techniques, the synergistic effects of surfactant and antenatal steroids, revised, or retired at or before that time. and surfactant therapy for respiratory disorders other than RDS. In PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). addition, the effect of CPAP on RDS and surfactant replacement and the Copyright © 2014 by the American Academy of Pediatrics 156 FROM THE AMERICAN ACADEMY OF PEDIATRICS Downloaded from www.aappublications.org/news by guest on September 29, 2021 FROM THE AMERICAN ACADEMY OF PEDIATRICS TABLE 1 Meta-analyses of Surfactant Replacement: Prophylaxis and Rescue Treatment With prophylactic surfactant versus rescue 2,3,8,11 Animal-Derived and Synthetic Surfactant surfactant.14 However, when the studies Outcome Prophylactic Surfactant Rescue Surfactant that allowed for routine application of Animal Derived Synthetic Animal Derived Synthetic CPAP were included in the meta-analysis N RR (95% CI) N RR (95% CI) N RR (95% CI) N RR (95% CI) (National Institute of Child Health and Human Development SUPPORT Trial and Neonatal mortality 8 0.60 (0.47–0.77) 7 0.70 (0.58–0.85) 10 0.68 (0.57–0.82) 6 0.73 (0.61–0.88) Pneumothorax 9 0.40 (0.29–0.54) 6 0.67 (0.50–0.90) 12 0.42 (0.34–0.52) 5 0.64 (0.55–0.76) Vermont Oxford Network Delivery Room PIE 6 0.46 (0.36–0.59) 2 0.68 (0.50–0.93) 8 0.45 (0.37–0.55) 4 0.62 (0.54–0.71) Management Trial), the benefits of pro- a BPD 8 0.91 (0.79–1.05) 4 1.06 (0.83–1.36) 12 0.95 (0.84–1.08) 5 0.75 (0.61–0.92) phylactic surfactant on mortality (RR BPD/deatha 8 0.80 (0.72–0.88) 4 0.89 (0.77–1.03) 12 0.83 (0.77–0.90) 4 0.73 (0.65–0.83) 0.89; 95% CI 0.76–1.04) and air leak (RR N, number; PIE, pulmonary interstitial emphysema. a Defined at 28 d. 0.86; 95% CI 0.71–1.04) could no longer be demonstrated.5 Furthermore, infants receiving prophylactic surfactant had efficacy of the INSURE approach (intuba- born at less than 27 weeks’ gestation, tion, surfactant administration, and ex- may be increased with surfactant a higher incidence of BPD or death than tubation to CPAP) are reviewed. therapy. Surfactant replacement is did infants stabilized on CPAP (RR 1.12; 95% CI 1.02–1.24). Secondary analyses effective for larger and more mature of studies that did or did not use CPAP PRETERM INFANTS AND preterm infants with established RDS. SURFACTANT EFFECTIVENESS IN to stabilize infants demonstrated a trend to a lower risk of intraventricular CLINICAL TRIALS PROPHYLACTIC VERSUS RESCUE – SURFACTANT hemorrhage (RR 0.91; 95% CI 0.82 1.00) Surfactant trials have included infants and severe intraventricular hemorrhage born between 23 and 34 weeks’ ges- A prophylactic, or preventive, surfactant (RR 0.87; 95% CI 0.70–1.04) with pro- tation and/or with birth weight be- strategy is defined as intubation and phylactic surfactant. That finding cannot tween 500 and 2000 g.1–12 The results surfactant administration to infants at be explained; however, there was con- of subgroup analyses from such stud- high risk of developing RDS for the siderable heterogeneity in the trials in- ies indicated that surfactant therapy primary purpose of preventing wors- cluded in the meta-analysis. The risks of decreased mortality rates most effec- ening RDS rather than treatment of developing other complications of pre- tively in infants born at less than 30 established RDS; this has been oper- maturity, such as retinopathy of pre- weeks’ gestation or with birth weight ationalized in clinical studies as sur- maturity, patent ductus arteriosus, and <1250 g.12 In addition, surfactant re- factant administration in the delivery periventricular leukomalacia, were not placement reduced the incidence of room before initial resuscitation efforts significantly different. pneumothorax, pulmonary interstitial or the onset of respiratory distress or, When studies investigating infants born emphysema, and the combined out- most commonly, after initial re- at <30 weeks’ gestation were analyzed come of death or BPD, compared with suscitation but within 10 to 30 minutes separately,5 similar findings were no surfactant replacement12;these after birth. This contrasts with a rescue noted. However, there was a trend for findings suggest that lung injury is or treatment surfactant strategy, in an increased risk of chronic lung dis- mitigated after surfactant replace- which surfactant is given only to pre- ease in infants born at <30 weeks’ ment. The incidence of other medical term infants with established RDS. gestation who received prophylactic morbidities, such as BPD, intraven- Rescue surfactant is most often ad- surfactant (RR 1.13; 95% CI 1.00–1.28) tricular hemorrhage, necrotizing en- ministered within the first 12 hours and a significant increase in death or terocolitis, health care–associated after birth, when specified threshold chronic lung disease (RR 1.13; 95% CI infections, retinopathy of prematurity, 1.02–1.25) with use of prophylactic and patent ductus arteriosus, has not criteria of severity of RDS are met. surfactant. changed with surfactant replacement, The meta-analysis of studies conducted but this may be attributable, in part, before routine application of CPAP EARLY VERSUS DELAYED to the large reduction in mortality demonstrated a lower mortality rate SELECTIVE SURFACTANT with surfactant replacement ther- (relative risk [RR] 0.69; 95% confidence TREATMENT OF RDS apy.13 The onset of clinical signs of interval [CI] 0.56–0.85; number needed patent ductus arteriosus may occur to benefit [NNTB] 20) and a decrease in Although there are no statistically earlier, and the incidence of pulmo- the risk of air leak (RR 0.79; 95% CI significant benefits to prophylactic use nary hemorrhage, especially in infants 0.63–0.98) in preterm infants receiving of surfactant when compared with PEDIATRICS Volume 133, Number 1, January 2014 157 Downloaded from www.aappublications.org/news by guest on September 29, 2021 prophylactic CPAP, several studies have CPAP without surfactant.15 When com- of surfactant protein B (SP-B). SP-B investigated whether administration of pared with the group of infants re- enhances the rate of adsorption of surfactant early in the course of re- ceiving prophylactic surfactant and phospholipids at the air-water inter- spiratory insufficiency improves clini- continued ventilation, the RR of death face, is involved in the formation of tu- cal outcomes.