Porcine-Derived Lung Surfactant

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Abstract
Porcine-derived lung surfactant (PLS; Curosur®) has shown efficacy in neonatal respiratory distress syndrome. PLS consists of phospholipids, mainly dipalmitoylphosphatidylcholine, the primary surface-active agent of natural lung surfactant, and pulmonary surfactant-associated proteins which facilitate spreading and adsorption of the surface-active agent at the air-alveolar interface. Intratracheal administration of a single dose of PLS 200 mg/kg significantly improves the survival rate and reduces the incidence of bronchopulmonary dysplasia at 28 days in premature infants (birthweight 700 to 2000g) with severe respiratory distress syndrome (fraction of inspired oxygen ≥ 0.60). PLS also reduces the incidence of air leak events such as pulmonary interstitial emphysema and pneumothorax. The response rate may be further improved by administration of additional 100 mg/kg doses at 12-hour intervals to infants showing a poor response or relapse after a single dose. PLS prophylaxis reduces the incidence and severity of respiratory distress syndrome in premature infants at high risk of developing the disease; however, it remains unclear whether the eventual clinical outcome is similar or superior to that observed in infants who receive rescue treatment. PLS is well tolerated and does not appear to increase the incidence of complications of prematurity or respiratory distress syndrome, including patent ductus arteriosus and intraventricular haemorrhage. Although its effect on long term development requires further investigation, early indications are that PLS is not associated with any long term adverse sequelae. Comparative trials are clearly warranted to determine the efficacy and toler-ability of PLS relative to that of other available surfactant preparations, particularly to explore preliminary indications that a more rapid effect of natural surfactants such as PLS (compared with synthetic products) may correlate with improved clinical outcomes, and that PLS may result in fewer complications than synthetic preparations. Thus, available data show PLS to be a very effective agent for the treatment and prophylaxis of neonatal respiratory distress syndrome, and that it may have some advantages over synthetic preparations. Endogenous lung surfactant lowers surface tension forces at the air-alveolar in-terface, thereby preventing the alveoli from collapsing during expiration. Its deficiency in premature infants due to lung immaturity at birth can lead to the development of neonatal respiratory distress syndrome. This disease affects about 60 to 70% of infants born at less than 30 weeks’ gestation and is associated with high morbidity and increased mortality. The risk of developing respiratory distress syndrome is increased by premature birth, male sex, delivery by caesarean section, being a second-born twin, familial history and maternal diabetes mellitus. Treatment consists of supplementary oxygen and mechanical ventilation to facilitate gas exchange, and replacement therapy with exogenous lung surfactant. Lung surfactant consists of phospholipids, which are the primary surface-active agents, and pulmonary surfactant-associated proteins, which facilitate adsorption, spreading and recycling of the surfactant within the lungs. Administration of artificial or natural exogenous surfactant preparations reduces the ventilatory requirement (which can cause complications such as pneumothorax and pulmonary interstitial emphysema) and significantly improves the clinical outcome in the majority of premature infants with respiratory distress syndrome. However, approximately 10 to 25% of infants show a poor response to surfactant replacement therapy, which may be due to lung immaturity, protein leakage across the alveolar-capillary membrane, disease severity, inadequate dosage, uneven distribution or insufficient levels of surfactant, perinatal asphyxia, patent ductus arteriosus or the presence of congenital infection. Whether there is an increased risk of infection and/or immunological sensitisation to foreign proteins and phospholipids found in exogenous surfactant preparations in infants remains unclear. Porcine-derived lung surfactant (PLS; CurosurfaR consists of approximately 99% polar lipids (mainly phospholipids) and 1% hydrophobic, low molecular weight proteins (surfactant-associated proteins B and C). The drug significantly improved lung expansion and gas exchange in preterm rabbit pups to a level similar to that seen in near-term ventilated pups and appeared more effective than various artificial surfactant preparations in this regard. PLS has also shown efficacy in adult guinea-pigs with severe respiratory insufficiency induced by lung lavage and in a rabbit model of meconium aspiration. Inhibition of the surface properties of PLS by plasma proteins (fibrinogen > haemoglobin > albumin) has been demonstrated in vitro at protein: surfactant concentration ratios of >1: 1. PLS administered as rescue therapy significantly improved clinical outcome in premature infants with severe respiratory distress syndrome [birthweight 700 to 2000g; fraction of inspired oxygen (FiO2) >- 0.60] in randomised multicentre trials. Compared with untreated controls, intratracheal administration of a single bolus of PLS 200 mg/kg 2 to 15 hours after birth caused significant improvements in gas exchange and oxygenation, which were evident within 5 minutes of drug administration. The 28-day mortality rate was significantly lower in PLS recipients versus untreated controls (31 vs 51%), the incidence of bronchopulmonary dysplasia in survivors was reduced by about 57% (23 vs 53%), and there was an increase in the combined incidence of survival without bronchopulmonary dysplasia compared with untreated controls (55 vs 26%). Administration of additional 100 mg/kg doses at 12-hour intervals to infants still requiring high supplemental oxygen after the first dose further reduced the 28-day mortality rate with or without bronchopulmonary dysplasia. Furthermore, the mortality rate was lower in infants treated at an earlier stage of the disease (Fi02 0.40 to 0.59) compared with late treatment once the disease became severe (FiO2 >- 0.60). PLS prophylaxis in premature infants (26 to 29 weeks’ gestation) significantly reduced the incidence and severity of respiratory distress syndrome compared with controls (incidence of severe respiratory distress syndrome 19 vs 36%), and reduced the 28-day mortality rate from 19 to 11%. However, the clinical outcome at 28 days did not differ significantly between infants receiving prophylaxis and those eligible for rescue treatment. Findings of a recent meta-analysis suggest that prophylaxis is more beneficial than rescue treatment; thus larger trials comparing the efficacy of these 2 treatment regimens are warranted, as are studies to identify subgroups of infants likely to receive the most benefit from PLS prophylaxis. While preliminary findings suggest that natural surfactants such as PLS may act more rapidly than synthetic surfactants, comparative clinical studies with other surfactant preparations are lacking. PLS administration has been well tolerated in multicentre clinical trials (including >2900 patients), in which it did not appear to increase the incidence of complications of prematurity or respiratory distress syndrome in premature infants (700 to 2000g birth weight). Premature infants treated with PLS had a lower incidence of pulmonary air leak events (pulmonary interstitial emphysema and pneumothorax), and the number of infants with patent ductus arteriosus, intraventricular haemorrhage, retinopathy of prematurity, pneumonia, septicaemia or necrotising enterocolitis did not appear to differ significantly between PLS recipients and untreated or historical controls. PLS does not appear to increase the incidence of apnoea of prematurity or pulmonary haemorrhage; however, this requires further study. Preliminary results at 2-year follow-up indicate that PLS administration at birth does not appear to affect the incidence of functional handicaps or overall growth and development compared with no treatment, and does not appear to adversely affect immunological sensitisation to lung surfactant compared with that observed in untreated controls. However, the longer term tolerability of surfactant replacement therapy as measured by effects on development remains unclear. PLS 100 or 200 mg/kg administered intratracheally as a single bolus (concentration 80 g/L; total volume 1.25 or 2.5ml) over a few seconds is recommended to treat premature infants with established respiratory distress syndrome (birth-weight 700 to 2000g). Infants still requiring supplemental oxygen 12 hours postdose (Fi02 > 0.40) may be given an additional 100 mg/kg dose, and a further dose (100 mg/kg) may be given 12 hours later if FiO2 remains above 0.40. Infants at high risk of developing respiratory distress syndrome may be treated with a single 100 or 200 mg/kg dose within 10 minutes of birth as prophylaxis.