Clinical review: Exogenous surfactant therapy for acute lung injury/acute respiratory distress syndrome--where do we go from here?
Bottom Line: Despite advances in clinical management, morbidity and mortality remains high.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.
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.
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Mentions: In patients with ARDS, dynamic surfactant assessment involves consecutive BALF analyses to demonstrate time-dependent changes in surfactant composition [11,22]. These studies have inherent limitations, including variable BALF recovery and lack of information regarding synthesis or turnover. Radio-isotope-labelling studies conducted in previous decades provided substantial knowledge regarding the nature of surfactant dynamics in animal models of lung injury, but these techniques are not applicable to the study of humans. Surfactant PC is synthesised from phospholipid precursors such as glucose, glycerol and choline via the cytidine diphosphate-choline pathway (Figure 1). By labelling these phospholipid precursors with stable (nonradioactive) isotopes, it is possible to assess surfactant PC synthetic rates and metabolism. 13C-labelled glucose and free fatty acids, such as labelled 13C-palmitic acid (16:0), have been used successfully to study surfactant metabolism in neonates . The fractional synthetic rates (percentage of newly synthesised surfactant per day) of disaturated surfactant PC (Palmitate 16:0) can be quantified using gas chromatography-isotope ratio mass spectrometry (GC-IRMS) by the detection of incorporated labelled 13C. However, fatty acid labelling only provides information regarding metabolism of that particular fatty acid in question and the assessment of 13C enrichment using GC-IRMS is not informative for the synthesis and metabolism of other individual surfactant PC species .