Abstract
Acute lung injury and acute respiratory distress syndrome (ARDS) are characterised by severe hypoxemic respiratory failure and poor lung compliance. Despite advances in clinical management, morbidity and mortality remains high. Supportive measures including protective lung ventilation confer a survival advantage in patients with ARDS, but management is otherwise limited by the lack of effective pharmacological therapies. Surfactant dysfunction with quantitative and qualitative abnormalities of both phospholipids and proteins are characteristic of patients with ARDS. Exogenous surfactant replacement in animal models of ARDS and neonatal respiratory distress syndrome shows consistent improvements in gas exchange and survival. However, whilst some adult studies have shown improved oxygenation, no survival benefit has been demonstrated to date. This lack of clinical efficacy may be related to disease heterogeneity (where treatment responders may be obscured by nonresponders), limited understanding of surfactant biology in patients or an absence of therapeutic effect in this population. Crucially, the mechanism of lung injury in neonates is different from that in ARDS: surfactant inhibition by plasma constituents is a typical feature of ARDS, whereas the primary pathology in neonates is the deficiency of surfactant material due to reduced synthesis. Absence of phenotypic characterisation of patients, the lack of an ideal natural surfactant material with adequate surfactant proteins, coupled with uncertainty about optimal timing, dosing and delivery method are some of the limitations of published surfactant replacement clinical trials. Recent advances in stable isotope labelling of surfactant phospholipids coupled with analytical methods using electrospray ionisation mass spectrometry enable highly specific molecular assessment of phospholipid subclasses and synthetic rates that can be utilised for phenotypic characterisation and individualisation of exogenous surfactant replacement therapy. Exploring the clinical benefit of such an approach should be a priority for future ARDS research.
Highlights
Acute respiratory distress syndrome (ARDS), first described by Ashbaugh and colleagues in 1967 [1], is a leading cause of morbidity and mortality in critically ill patients
ARDS/acute lung injury (ALI) may result from both direct lung injury and indirect lung injury [3], causing significant phenotypic heterogeneity among patients
Possible explanations for the negative results from surfactant replacement studies in ARDS No large randomised controlled trial (RCT) of exogenous surfactant replacement has shown reduced mortality from this intervention (Table 5). This finding has been confirmed by a recent systematic review and meta-analysis that included nine RCTs with a total of 2,575 patients, which found no evidence of a mortality benefit
Summary
Acute respiratory distress syndrome (ARDS), first described by Ashbaugh and colleagues in 1967 [1], is a leading cause of morbidity and mortality in critically ill patients. 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]. Possible explanations for the negative results from surfactant replacement studies in ARDS No large RCT of exogenous surfactant replacement has shown reduced mortality from this intervention (Table 5) This finding has been confirmed by a recent systematic review and meta-analysis that included nine RCTs with a total of 2,575 patients, which found no evidence of a mortality benefit. Bronchoscopic sequential segmental administration of natural bovine surfactant was associated with improved PaO2/FiO2 ratios coupled with improved ventilation–perfusion matching in the lungs [50], as well
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