Oxide, superoxide and nitric oxide, are released by enzymatic reactions (xanthine oxidase/glucose oxidase/nicotinamide adenine dinucleotide phosphateSurfactant replacement in ARDS/ALI Fujiwara and colleagues reported the first positive, uncontrolled, clinical study of surfactant replacement in 1980 [37]. In this study, 10 premature neonates with severe respiratory distress syndrome were successfully treated with natural bovine surfactant supplemented with Q-VD-OPh site synthetic DPPC and phosphatidylglycerol. Subsequent randomised clinical trials (RCTs) with both natural and synthetic surfactant preparations have shown consistent improvements in lung mechanics, oxygenation and mortality in neonatal respiratory distress syndrome [38]. Several RCTs of surfactant replacement in adults with ARDS have been conducted since 1994 [39-46]. These generally have shown improvements in oxygenation indices but have failed to produce any demonstrable survival benefits [47]. An initial phase I study of synthetic surfactant composed of DPPC without any surfactant proteins (Exosurf ) demonstrated its safety profile in 51 patients with sepsisinduced ARDS [39]. In this study, surfactant was nebulised for 5 days continuously and a trend towards mortality benefit was seen in the treatment group. A subsequent larger RCT using the same methods with the same surfactant preparation and study population failed to show any benefits in oxygenation, mortality, length of ICU stay or duration of mechanical ventilation [40]. These negative results may be explained by the lack of surfactant proteins in the surfactant preparation leading to reduced surface spreading characteristics and poor alveolar surfactant deposition by this delivery method (estimated only 5 deposition) [40]. Gregory and colleagues performed a phase II RCT using bovine lung extract containing phospholipids, neutral lipids, fatty acids and surfactant proteins SP-B and SP-C in patients with ARDS. This study enrolledDushianthan et al. Critical Care 2012, 16:238 http://ccforum.com/content/16/6/Page 5 ofpatients and demonstrated improved oxygenation and a trend towards reduced mortality in the surfactant group [41]. A European-based multicentre RCT using a large bolus tracheal instillation of freeze-dried natural porcine surfactant (HL-10) failed to show any mortality benefit. This surfactant preparation consisting of phospholipids (90 to 95 ) and SP-B and SP-C (1 to 2 ) was instilled for up to three doses (totalling 600 mg/kg). This study of 418 ARDS/ALI patients was terminated early due to an excess of serious adverse events, such as hypotension and hypoxemia, in the treatment group [42]. Spragg and colleagues conducted three RCTs with a surfactant preparation consisting of phospholipids and recombinant SP-C. Following positive results from an animal study [48], a phase II study of recombinant SP-C in 40 ARDS patients showed a good safety profile [43]. This study was followed by a large multicentre phase III RCT of 448 ARDS patients, which showed improved oxygenation but no overall mortality benefit in the treatment group [44]. However, post hoc analysis demonstrated a trend towards mortality benefit for those patients with direct lung injury from aspiration and pneumonia [44]. Following this study, a further phase III RCT was conducted in a large cohort of patients (844 patients) with severe hypoxemia PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/26740125 secondary to aspiration and pneumonia. There was no mortality benefit and the study was terminated early due to fu.