Prophylactic surfactant treatment for respiratory distress syndrome in preterm lambs: Comparison of a novel peptide-containing synthetic surfactant (Synsurf) with porcine-derived surfactant (Curosurf®).

J Smith, JM van Zyl, DM Barry, G Maritz. Stellenbosch University & Tygerberg Children\'s Hospital, Departments of Paediatrics & Child Health & Pharmacology, 7505, South Africa

Introduction: In saline-lavaged (surfactant-depleted) adult rabbits, significant improvement in systemic oxygenation and shunt occurred after the instillation of a synthetic peptide-containing surfactant (Synsurf) compared to Exosurf® and Exosurf® + Ca. Adult animal models of surfactant depletion are not fully representative of the neonatal respiratory distress syndrome (RDS), whilst some preterm models for testing surfactant do not give the same results when directly compared. RDS in the preterm lamb closely resembles that of the human infant with the advantages being the ability to measure multiple variables for the lungs and other systems over extended periods.

Objective of the study: To investigate if a novel peptide-containing synthetic surfactant (Synsurf) leads to improved systemic oxygenation, lung mechanics, radiology and histology in comparison to a commercially available porcine-derived lung surfactant (Curosurf, Chiesi Pharmaceutici, Italy) when administered before first breath

Design: Randomized, animal study.

Methods: A cesarean section under general anesthesia was performed on 18 time-dated pregnant Dohne-Merino ewes at 129 -130 days gestational age (normal gestation 150 days). The fetal head was exposed, a tracheotomy performed and an uncuffed 4 or 4.5 mm endotracheal tube placed. Ten to 20 ml of fetal lung fluid was sampled to determine lung maturity. The umbilical cord was cut; animals were then delivered, dried, weighed, anesthetized, sedated and paralyzed. Too minimize lung injury ventilation with an expiratory tidal volume (Vtexp) of 6 - 8 ml/kg was used for the first 30 minutes. Vtexp was then increased to 8-10ml/kg. Hereafter ventilator settings were held constant throughout the study at an FiO2 of 1.0, rate 40 bpm, Ti 0.70 sec and Peep 4 cm H2O. Lambs were assigned to one of 3 groups (n=6 lambs/group) within 2 minutes of delivery. Two surfactants were tested: Synsurf (combination of poly-L-Lysine and poly-L-Glutamic acid, DPPC and PG) and Curosurf® (both at 100mg/kg DPPC) and a group treated with normal saline. Measurements of physiological variables, blood gases, lung mechanics and pulmonary arterial pressure (PAP), were made before and after surfactant and saline replacement, and at 15, 30, 45, 60, 90, 120, 180, 240 and 300 min after treatment. After 5 hours, all live animals were killed. Lungs of all the animals were removed for histology, wet-dry weight and morphometry.

Statistical analysis: STATISTICA was used to determine comparability of the experimental groups before and after surfactant instillation. Non-parametric methods were used and data are summarized as means±SD. Significant differences were accepted at p-values < 0.05

Results: At randomization, arterial blood gases, ventilator indices and hemodynamic variables were similar for all 3 groups. All lambs were severely surfactant-deficient as per lamellar body counts (<15000/µL), L/S ratios (<2) and Cdyn. Following instillation of vehicle, all 3 groups experienced significant improvement in oxygenation within 30 minutes. At 30 minutes, the Synsurf-group had a significantly higher PaO2 values (p=0.03) compared to that of Curosurf and saline treated animals. Both surfactant treated groups showed better oxygenation between 30 and 240 min compared to the saline-treated group. Synsurf treated animals had a sustained and significantly better oxygenation status at 300min compared to the others (Synsurf PaO2 288±137.1mmHg vs Curosurf PaO2 133.75±110.6mmHg vs Saline PaO2 190.9±149.5mmHg; p<0.05). Dynamic compliance (Cdyn [ml/cmH2O/kg]) improved over time, with no inter-group differences at 300min (Synsurf Cdyn 0.45±0.09 vs Curosurf Cdyn 0.48±0.05 vs saline Cdyn 0.47±0.07). All of the surfactant treated animals survived and one in the saline group died before study-end. Histology between groups was not different, showing mild-moderate injury patterns. Lung wet-dry weight ratios were similar between groups (Synsurf 6.47±1.55 vs Cursosurf 5.66±1.11 vs Saline 6.22±0.65; p=ns).

Conclusions: Treatment with surfactants before first breath clearly resulted in improved systemic oxygenation, with the response of Synsurf-treated animals being more sustained at 300 min. In vivo mechanisms explaining this response for the synthetic surfactant group may be related to the amphiphilic character of the peptide complex.