Key messages

• Pulmonary surfactant lowers the alveolar surface tension and makes breathing possible at normal transpulmonary pressures.

• In acute respiratory distress syndrome (ARDS) both composition and surface activity of pulmonary surfactant are markedly altered, yielding elevated alveolar surface tension values.

• In pilot studies, application of 300 to 800 mg/kg of natural surfactant resulted in an acute improvement of gas exchange and slightly reduced 28-day mortality in ARDS.

Pulmonary surfactant is a lipoprotein complex covering the alveolar surface. By profoundly reducing the surface tension at the air-liquid interface, it prevents alveoli from collapse, particularly during expiration. It consists of approximately 90 per cent lipids (mostly phospholipids and a small amount of neutral lipids) and 10 per cent proteins. The phospholipid fraction comprises approximately 80 per cent phosphatidylcholine (mostly dipalmitoylated) and approximately 10 per cent phosphatidylglycerol. Four surfactant-specific apoproteins (surfactant proteins A, B, C, and D) have been identified. Triggered by inspiratory stretching of the alveolar cell layer, alveolar type II cells secrete surfactant-containing lamellar bodies which are extracellularly reorganized into tubular myelin and large multilamellar vesicles, termed large surfactant aggregates. Adsorption of the phospholipids to the air-liquid interface results in the formation of a stable phospholipid film, which, upon compression, can reduce the surface tension to almost zero. In addition to dipalmitoylated phosphatidylcholine and phosphatidylglycerol, surfactant proteins B and C appear to play an essential role in this process. The periodic compression and re-expansion of the interfacial phospholipid film provokes permanent refinement, with the large surfactant aggregates being converted into unilamellar vesicles (small surfactant aggregates). Additional functions of the alveolar surfactant system include prevention of the formation of alveolar edema fluid and, although currently at best fragmentary, a considerable impact on the alveolar host-defense mechanisms.

A lack of surface-active material is the primary cause of the infant respiratory distress syndrome (IRDS), and surfactant therapy (50-100 mg/kg) is now the gold standard. In contrast, surfactant deficiency does not seem to be of major importance in the acute respiratory distress syndrome (ARDS), which is characterized by overhelming inflammatory processes at the gas exchange unit. Rather, a broad pattern of biochemical and biophysical abnormalities of the pulmonary surfactant system is observed, which favors alveolar collapse with ventilation-perfusion mismatch and, in particular, shunt flow. Analysis of bronchoalveolar lavage fluids from ARDS patients consistently demonstrated a decrease in the surface-tension-reducing properties, with minimum surface tension values being increased to above 15 to

20 mN/m compared with near zero in healthy controls (Günther et ai 1996). Several biochemical changes have been observed in these patients, including the following.

1. The phospholipid profile is altered, with a reduction in the relative percentages of phosphatidylcholine and phosphatidylglycerol and an increase in the percentages of phosphatidylinositol, phosphatidylethanolamine, and sphingomyelin.

2. The fatty acid composition is altered, with a marked reduction in the relative content of saturated fatty acids, particularly palmitic acid species, in the phospholipid fraction.

3. The levels of surfactant apoproteins are decreased, as shown for the hydrophilic surfactant protein A in native bronchoalveolar lavage fluid and surfactant protein B in the large surfactant aggregate fraction.

4. The content of large surfactant aggregates is reduced. Several experimental studies have suggested that induction of an acute lung injury will result in a higher abundance of the small surfactant aggregates at the expense of the large aggregates. Accordingly, a reduction in the relative content of large surfactant aggregates was demonstrated in ARDS.

5. Surfactant function is inhibited by leaked plasma proteins. Leakage of plasma proteins into the alveolar space is a common finding in ARDS. The ratio of phospholipid to protein in bronchoalveolar lavage fluid is normally about 0.5 (by weight), but reaches mean values as low as 0.05 in ARDS. Strong surfactant-inhibitory capacity has been demonstrated for albumin, hemoglobin, fibrinogen, and particularly fibrin which is known to be easily generated in the alveolar space of ARDS patients because of increased procoagulant and antifibrinolytic activities.

6. Surfactant function is inhibited by inflammatory mediators, particularly proteases and oxygen radicals released by inflammatory cells, which may primarily attack the functionally important hydrophobic surfactant proteins B and C. A corresponding scenario of complex surfactant disturbances, as described for ARDS primarily triggered by diseases remote from the lung (e.g. sepsis, polytrauma, pancreatitis), has also been observed under conditions of severe pneumonia necessitating mechanical ventilation.

Against this background, restoration of alveolar surfactant function appears to be a reasonable approach to improving gas exchange in ARDS patients. Such attempts may include pharmacological approaches to stimulate the secretion of intact surfactant material from type II pneumocytes, but there is no clear evidence that this approach can be effectively used under conditions of acute respiratory failure. In addition, transbronchial administration of exogenous (natural) surfactant preparations may also be employed in ARDS, but large quantities of material will be required to overcome the surfactant-inhibitory capacities in the alveolar space under these conditions. Gl.§99H...M @L (1997) noted some improvement in gas exchange upon intratracheal instillation of 400 to 800 mg/kg of Survanta (Table 1), and increased survival was suggested in the group receiving 400 mg/kg. Walmrath etal (1996) investigated the safety and efficacy of a bronchoscopic application of another natural surfactant extract (Alveofact) in patients with severe ARDS mostly due to sepsis and severe pneumonia. All patients (currently 26) fulfilled extracorporeal membrane oxygenation criteria (mean Murray lung injury score approximately 3.3) and were treated within the first 5 days of disease, i.e. before the onset of major fibrotic processes. As is evident from Table.!,, administration of surfactant resulted in a rapid increase in the mean PaO2/FiO2 ratio, with a concomitant reduction in the intrapulmonary shunt flow. More than two-thirds of the patients 'responded' with a PaO2/FiO2 increase of at least 25 per cent. The effect was partially lost within the following hours in some of the responders, but was restored with prolonged improvement of arterial oxygenation by a second administration (data not given in detail). Analysis of the surfactant properties in bronchoalveolar lavage fluid obtained before and after surfactant administration suggested impressive, but still incomplete, restoration of surfactant properties. In contrast, An?.y§io §L§l (1996) found no clinical effect following aerosol application of Exosurf for 5 days in ARDS

patients compared with a group receiving saline aerosol. However, there were major drawbacks to this study. Firstly, the authors estimated a pulmonary deposition of 5 mg DPPC/day in their patients. Even if a higher relative efficacy of nebulized versus instilled surfactant material is assumed, this amount of surfactant is clearly far too low to exert a significant clinical response. Secondly, Exosurf, a surfactant-apoprotein-free synthetic surfactant preparation, has repeatedly been shown to possess high sensitivity towards inhibition by plasma proteins and thus might have a lower efficacy than natural surfactant preparations in ARDS.

Table 1 Gas exchange and surfactant properties upon surfactant administration in ARDS.

In conclusion, profound alterations of the alveolar surfactant system are encountered in ARDS, which contribute to the severe impairment in gas exchange. Transbronchial administration of surfactant by bronchoscopy may offer a feasible and safe approach to improving the biochemical and biophysical properties of the endogenous surfactant pool and hence the gas exchange conditions in most severe early-stage ARDS. However, a high and/or repetitive dosage regimen appears to be necessary to overcome inhibitory capacities in the alveolar space of these patients and to achieve sustained alveolar recruitment. Forthcoming studies will have to identify the optimum timing and dosage regimen of this intervention and will have to address the question of whether this therapy is capable of reducing the high mortality of patients with severe ARDS.

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