New targets for surfactant replacement therapy: experimental and clinical aspects.

The benefits of surfactant replacement therapy for neona-tal respiratory distress syndrome (RDS) have been well documented in several randomised trials, and this treatment is now part of routine clinical management of babies with immature lungs. Meta-analysis of data from a large number of babies treated in controlled trials has confirmed lower mortality and reduced incidence of complications , especially pneumothorax. This is also the case when surfactant is administered prophylactically to babies at risk soon after birth. These beneficial effects have been obtained with modified, natural, as well as with protein free synthetic surfactants.' The pathophysiology of neonatal RDS is characterised by a combination of surfactant deficiency and surfactant inactivation as a result of plasma proteins leaking into the air spaces from areas of epithelial disruption. Surfactant may be inactivated or deficient in other forms of lung disease as well, including meconium aspiration syndrome (MAS), pneumonia, lung hypoplasia, the "adult" type of acute respiratory distress syndrome (ARDS), and pulmonary haemorrhage. In this article I intend to outline experimental and clinical evidence indicating that these various diseases constitute potential new targets for surfac-tant replacement therapy. Meconium aspiration syndrome Aspiration of meconium elicits a complex series of patho-physiological events characterised by mechanical obstruction of airways, "chemical pneumonitis," and inactivation of surfactant. Meconium contains several components which interfere with surfactant function, including cholesterol , free fatty acids, and bilirubin.2 ' The inhibitory effect of meconium is dose dependent, but not simply due to the stoichiometric relation between inhibitor and surfactant. Low concentrations of surfactant are therefore relatively more sensitive to inhibition than high concentrations. For example, when examined with a pulsating bubble, modified natural surfactant at a concentration of 1.5 mg/ml is completely inactivated by a meconium concentration of 65 jg/ml. At a twofold higher surfactant concentration (3 mg/ml), as much as 1300 tg/ml of meconium is required to obtain the same inhibitory effect.2 Thus increasing the pool size of surfactant in the air spaces of a baby with MAS may not only counterbalance the presence of inhibitors but also makes the surfactant system relatively more resistant to inhibition. This is the rationale for surfactant therapy in MAS. Promising effects of surfactant administration have been documented in animal models of MAS. Treatment with the clinically recommended dose of Curosurf improves lung compliance, gas exchange, and alveolar expansion in newborn rabbits 4 and adult rats 5 with experimental meco-nium aspiration but does not restore …