Exogenous surfactant in acute respiratory distress syndrome: more is better.

Pulmonary surfactant is a complex of highly active phospholipids and proteins that cover the alveolar epithelial surface of the lungs [1]. Surfactant is synthesized in the alveolar type-II cells, stored in the lamellar bodies, and secreted to the alveolar space where it undergoes complex changes [2]. The composition of lung surfactant in humans is very constant, although it may change in disease states [3]. Phospholipids account for 85% of its composition and the main component is dipalmitoylphosphatidylcholine (DPPC). In addition, surfactant contains different apoproteins, neutral lipids, and carbohydrates [4]. Pulmonary-surfactant dysfunction can lead to acute lung injury and is characterized by alveolar instability, floating, and collapse. These abnormalities have been shown to occur in acute respiratory distress syndrome (ARDS) [5, 6] and infant respiratory distress syndrome (IRDS) [7]. Since the initial report of ARDS by ASHBAUGH et al. [5], abnormalities of the surfactant system have been recognized. PETTY and co-workers [8, 9], later reported both qualitative and quantitative abnormalities in the surfactant content of ARDS patients. It is now known that surfactant dysfunction plays a major role in the pathophysiology of ARDS [6, 10], and functional changes have been described not only in patients with established ARDS, but also in patients at risk [10–12]. The main biochemical abnormalities include an 80% fall in the total phospholipid content, decline in the fractional content of DPPC and phosphatidylglycerol and other fractions, and loss of apoproteins (90% of surfactant protein (SP)-A and SP-B) [6, 7]. This loss of alveolar surfactant is due to several factors including the presence of plasma proteins [13], cleavage of phospholipids by serum phospholipases [14], formation of free radical species (including nitrates, lipid peroxidation, etc.) [15–17], and conversion to nonfunctional surfactant with more phospholipid aggregates [14]. Exogenous-surfactant replacement has been successfully achieved in IRDS [7], but clinical trials in ARDS have had mixed results. Initial preliminary reports, mainly phase-II multicentre trials, have shown that exogenous artificial surfactant (Exosurf1) [18] or bovine surfactant (Survanta1) [19] in ARDS can improve oxygenation and lung mechanics. The authors9 group reported the results of a large, randomized, multicentre, prospective trial involving 725 patients in sepsis-induced ARDS treated with Exosurf1 or placebo [20]. This study did not show any improvement in either oxygenation and/or survival benefit of exogenous-surfactant supplementation. There have been several speculations as to why the Exosurf1 trial failed to show any improvement in the physiological parameters and/or survival in patients with ARDS. One explanation could be related to the underlying condition that resulted in ARDS. In the study by GREGORY et al. [19], patients had several precipitating aetiologies to ARDS whereas the Exosurf1 study was limited to sepsis-induced ARDS. Thus, the aetiology of ARDS may have to be taken into consideration when future studies are designed. Another potential explanation for the difference in the results, could be related to the surfactant preparation that was utilized. Exosurf1 is an exogenous surfactant that does not contain apoproteins and this can affect the onset of action and be inhibited by serum proteins. The study by GREGORY et al. [19] used a bovine surfactant that contains two apoprotein constituents, whereas the synthetic preparation contains neither protein nor peptides and needs to achieve an in vitro critical concentration in order to exert its effects [16]. These data suggest that for an exogenous surfactant preparation to be effective, it must contain apoproteins. Finally, the mode of delivery of surfactant may be crucial. In the Exosurf1 trial [20], surfactant was delivered by continuous aerosolization, but MACINTYRE et al. [21], showed that only 4.5% of aerosolized radiolabelled surfactant reached the lungs thus,w5 mg of 102 mg of aerosolized DPPC?kg?day actually reached the lungs in this study. It is also possible that the small amount of delivered surfactant was inhibited by the same inflammatory mediators associated with ARDS, and therefore had no effect. In this issue of the European Resipratory Journal, GÜNTHER et al. [22] reported on the results of 27 patients with ARDS who received 300 mg?kg of body weight of natural bovine surfactant extract (Alveofact1) delivered to each segment of the lung via a fibreoptic bronchoscope. This study showed that using the bronchoscope to deliver surfactant had no deleterious effects on gas exchange, lung mechanics, Dept of Medicine, Division of Pulmonary Medicine/Critical Care Medicine, The University of Texas Health Science Centre at San Antonio and the South Texas Veterans Health Care System, Audie L. Murphy Division, San Antonio, TX, USA.