Surfactant as treatment for acute lung injury (ALI) has been under investigation for almost two decades, and despite considerable effort, progress has been slow. While the rationale for this intervention is strong, the hurdles to demonstrating clinical efficacy are immense. These hurdles are not unique to studies of surfactant therapy, but face all treatments proposed for ALI. In fact, no pharmacologic therapy for that syndrome is of proven benefit despite evaluation in phase III trials of over a dozen candidates, and current treatment consists of supplemental oxygen and mechanical ventilation. Yet progress is being made in the attempt to establish the efficacy of surfactant therapy for patients with ALI.

Pulmonary surfactant, a complex mixture of phospholipids, neutral lipids and proteins, results in a lowering of alveolar surface tension during ventilation, thereby markedly reducing the work of breathing. In addition, it helps maintain the patency of small airways, protects against formation of lung edema, and participates in local defense of the lung against infection. In the setting of acute lung injury (ALI), there are marked changes in lung surfactant that combine to result in a dramatic loss of function. These changes include: marked reduction in surfactant production by alveolar type II cells; inactivation by plasma proteins in alveolar edema fluid of the inflamed lung; and inactivating reaction of surfactant lipids and/or proteins with reactive nitrogen and oxygen species, proteases, and phospholipases. In addition, the extracellular conversion of large (functional) surfactant aggregates to small (inactive) aggregates is augmented. Loss of surfactant function results in decreased pulmonary compliance and functional residual capacity, atelectasis, increased right-to-left shunt and hypoxemia, and possibly enhanced edema formation. As these changes are all features of ALI, it is reasonable to postulate that loss of surfactant function may contribute to the pathophysiology of ALI. The jump to postulating that treatment with exogenous surfactant may improve survival rests on several observations. First, in a variety of animal models, loss of surfactant function results in an ALI-like syndrome, and treatment with exogenous surfactant results in improved gas exchange. Second, in phase III clinical trials, treatment of patients with ALI with exogenous surfactant resulted in improved gas exchange (1) and, in a study