Randomized European Multicenter Trial of Surfactant Replacement Therapy for Severe Neonatal Respiratory Distress Syndrome: Single Versus Multiple Doses of Curosurf

¹ From the Department of Pediatrics, University of Göttingen, Germany
² Research Unit for Experimental Perinatal Pathology and St Göran's Children's Hospital, Stockholm, Sweden
³ From the Department of Clinical Chemistry, Danderyd Hospital, Stockholm
⁴ Royal Maternity Hospital, Belfast, Northern Ireland
⁵ From the Department of Medical Statistics, Department of Pediatrics, University of Göttingen
⁶ Academisch Ziekenhuis, Amsterdam, Netherlands
⁷ From the Department of Pediatrics, University of Bochum, Germany
⁸ From the Department of Pediatrics, University of Bonn, Germany
⁹ From the Department of Pediatrics, Community Hospital, Braunschweig, Germany
¹⁰ From the Department of Pediatrics, Central Hospital, Bremen, Germany
¹¹ From the Department of Pediatrics, University of Essen, Germany
¹² From the Department of Pediatrics, University Hospital, Graz, Austria
¹³ From the Department of Pediatrics, University Hospital, Groningen, Netherlands
¹⁴ From the Department of Pediatrics, Pediatric Hospital (Auf der Bult), Hannover, Germany
¹⁵ From the Department of Pediatrics, Community Hospital, Köln, Germany
¹⁶ From the Department of Pediatrics, Community Hospital, Mannheim, Germany
¹⁷ From the Department of Pediatrics, University of Paris, France

There is now convincing evidence that the severity of neonatal respiratory distress syndrome can be reduced by surfactant replacement therapy; however, the optimal therapeutic regimen has not been defined. This randomized European multicenter trial was designed to determine whether the beneficial effects of a single large dose of Curosurf (200 mg/kg) in babies with severe respiratory distress syndrome (arterial to alveolar oxygen tension ratio 0.10) could be enhanced by using multiple doses of surfactant. Preterm neonates (birth weight 700 to 2000 g) with severe respiratory distress syndrome requiring artificial ventilation with fraction of inspired oxygen 0.6 were randomized into two groups at an age of 2 to 15 hours. Both groups received the usual dose of Curosurf(200 mg/kg) immediately after randomization. In neonates randomized to receive multiple-dose treatment, two additional doses of Curosurf (100 mg/kg each) were instilled into the airways (12 and 24 hours after the initial dose) provided that the patients still needed artificial ventilation with fraction of inspired oxygen >0.21. In both groups (single dose: n = 176, multiple doses: n = 167) there was a rapid improvement in oxygenation as reflected by a threefold increase in arterial to alveolar oxygen tension ratio within 5 minutes after surfactant instillation (P < .001), and peak inspiratory pressure and mean airway pressure could be reduced significantly during the first 6 hours after surfactant treatment. In addition, ventilatory requirement (peak inspiratory pressure, ventilatory efficiency index) was reduced in the multiple-dose group 2 to 4 days after randomization (P < .05 to .01). Sixty-five percent of the patients randomized to the multiple-dose regimen and 68% of the single-dose group needed supplemental oxygen 12 hours after the first treatment. Analysis of 28-day outcome data showed a reduction of the incidence of pneumothorax in the multiple-dose group (9% vs 18%, P < .01). The primary end point, of combined incidence of mortality and bronchopulmonary dysplasia, was 33% in the single-dose group and 27% in the multiple-dose group (P = .08). Mortality at 28 days was reduced from 21% in the single-dose group to 13% in the multiple-dose group (P < .05 by logistic regression). It is concluded that treatment with multiple doses of surfactant is more effective than single-dose treatment in severe neonatal respiratory distress syndrome, further reducing pneumothorax mortality.

Key Words: respiratory distress syndrome • pulmonary surfactants • neonates

Submitted on March 12, 1991
Accepted on June 13, 1991

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