Multiple versus single doses of exogenous surfactant for the prevention or treatment of respiratory distress syndrome

Several randomized controlled trials demonstrated the effectiveness of surfactant therapy in the treatment or prevention of respiratory distress syndrome (RDS) in premature infants. It is widely accepted that surfactant administration decreases the severity of respiratory distress and the frequency of pneumothorax, and it also increases survival free from chronic lung disease and reduces mortality. The initial trials of surfactant replacement therapy evaluated, in most cases, surfactant administered in a single dose, identifying rapid improvements in oxygenation and ventilatory requirement. However, it was observed that, in many of these single dose studies, the clinical impact was less than expected. For instance, some studies described a group of neonates responding only transiently to surfactant therapy, possibly because of surfactant inhibition or inactivation. This observation led investigators to attempt multiple dose therapy.
This review of the Cochrane Collaboration, an independent no-profit organization conducting systematic meta-analyses in evidence-based medicine, evaluated randomized controlled trials comparing multiple doses of surfactant and single doses of surfactant extract in premature infants at risk for or having RDS.
In particular, the main objective of this analysis was to determine the different effects of multiple doses of exogenous surfactant compared to a single dose of exogenous surfactant on mortality and complications of prematurity. Secondary objectives included subgroup analyses according to treatment strategy, surfactant preparation [synthetic surfactant (non-protein containing), protein containing synthetic surfactant, animal derived surfactant extract], and gestational age. The search for randomized trials included Medline (from 1966 to June 2008), Cinhal, EMBASE and the Cochrane Central Register of Controlled Trials. Reviews including cross references, abstracts, conference and symposia proceedings, expert informants, and journal hand searching in the English language were also considered. Randomized controlled trials comparing the administration of multiple doses of surfactant to single doses of surfactant extract in premature infants at risk for or having RDS were selected for data analysis. Data on clinical outcomes including reactive airway disease, pneumothorax, patent ductus arteriosus, necrotizing enterocolitis, intraventricular hemorrhage (all intraventricular hemorrhage and severe intraventricular hemorrhage), bronchopulmonary dysplasia, retinopathy of prematurity, pulmonary hemorrhage, periventricular leukomalacia, neurodevelopmental follow-up, rehospitalization for pulmonary reasons, and mortality were excerpted and analyzed according to the standards of the Cochrane Neonatal Review Group.
In total, 3 trials met study criteria. Two studies were randomized controlled trials of multiple versus single dose animal derived surfactant extract in infants with established RDS. Meta-analysis of these trials suggests a reduction in the risk of pneumothorax [typical relative risk (RR) 0.51; 95% confidence interval (95% CI): 0.30-0.88] and a trend towards a reduction in the risk of mortality (typical RR 0.63; 95% CI 0.39-1.02). The other study compared multiple versus single dose synthetic surfactant in infants at high risk of RDS. This study reported a decrease in NEC (RR 0.20, 95% CI 0.08-0.51) and mortality (RR 0.56, 95% CI 0.39-0.81) No data on long-term neurological or pulmonary outcome were reported in any trial. No complications associated with multiple dose treatment were reported in the identified trials. Authors concluded that, in infants with established RDS, a policy of multiple doses of animal derived surfactant extract results in greater improvements regarding oxygenation and ventilatory requirements, a decreased risk of pneumothorax and a trend toward improved survival. In infants at high risk of RDS, multiple doses of synthetic surfactant resulted in greater improvements regarding oxygenation and ventilatory requirements, a decreased risk of NEC and decreased mortality than single doses.
These results have important implications in clinical practice. Since a more sustained response and an important improvement in clinical outcomes were observed in infants with RDS who are treated with multiple doses of exogenous surfactant, this approach appears the most desirable therapeutic strategy to RDS treatment.

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