ARDS/surfactant editorial..
I can PM the actual paper if anyone interested..very long and not sure of the interest..hi> gotta' love NEJM's sense of humor<g>
Exogenous Surfactant Replacement in ARDS — One Day, Someday, or Never?
Simon V. Baudouin, M.D.
Most therapies that fail to show benefit in well-conducted, randomized, controlled trials are abandoned by both clinical investigators and pharmaceutical companies. Treatment with exogenous surfactant for the acute respiratory distress syndrome (ARDS) appears to enjoy a different status. In this issue of the Journal, Spragg and coworkers (pages 884–892) present the results of two multicenter trials of recombinant surfactant therapy in ARDS, showing no significant difference in mortality between the groups of patients who received surfactant and those who received placebo. This report follows a number of other clinical studies, including a large, negative, multicenter, randomized, controlled trial that was published in the Journal in 1996.1 Why, then, do investigators and pharmacologists persevere with this line of research?
ARDS is a syndrome of reduced pulmonary gas exchange caused by diffuse injury to the alveolar–capillary barrier.2 The alveolus is filled with proteinaceous fluid, and there is a marked infiltrate of acute inflammatory cells. ARDS occurs after both indirect lung injury (e.g., sepsis) and direct lung injury (e.g., aspiration) and is associated with mortality of about 40 percent. The alveolar damage in ARDS causes a profound change in lung mechanics. Alveolar units lose their stability and readily collapse, particularly at low lung volumes. In the early stage of the disease, these collapsed units may be "recruited" back into functional use by ventilatory maneuvers including the intermittent use of high tidal volumes and the continuous use of positive end-expiratory pressure. This pathophysiology resembles experimental surfactant depletion and the natural surfactant deficiency that occurs in neonatal respiratory distress syndrome.
Experiments that began in the 1920s, as well as theoretical calculations regarding the surface forces that act on alveoli, indicated that the air–liquid interface within the gas-exchanging units had unusual properties. First, the surface tension of the alveolar lining fluid was considerably lower than that of free water, and second, the surface tension changed as the surface area of the air–liquid interface expanded or contracted. Lung lavage removed the surface-active compound, and the components of surfactant were subsequently identified. Surface tension at the air–liquid interface accounts for more than half of the elastic recoil of the healthy lung. Surfactant therefore substantially contributes to lung compliance, minimizes fluid accumulation within the alveoli, and helps to maintain a uniform alveolar size during ventilation.
Natural surfactant is a complex biologic substance with a composition that is remarkably consistent among species.3 Approximately 90 percent of surfactant consists of lipids, and 10 percent of proteins. One phospholipid, dipalmitoylphosphatidylcholine (DPPC), constitutes the major surface-tension–reducing component. Surfactant follows a complex life cycle in the lung (see Figure). It is initially synthesized by type II alveolar epithelial cells and stored in lamellar bodies. These bodies are released and, in the thin fluid layer covering the epithelium, form tubular myelin. The surface-active monolayer is subsequently formed from the transitional tubular myelin. Surfactant is recycled through the formation of small vesicles from the monolayer. These are subsequently absorbed by type II epithelial cells and macrophages.
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Figure. Surfactant Production and Recycling in the Normal Alveolus (Panel A) and Changes in Surfactant Metabolism in Acute Lung Injury (Panel B).
In the normal alveolus, surfactant is synthesized and packaged into lamellar bodies in the cell cytoplasm. These lamellar bodies then migrate to the cell membrane, with which they fuse, and then are released into the air–fluid interface within the alveolus. They subsequently form an intermediate tubular stage of surfactant called tubular myelin, which finally produces the functional coating layer. Surfactant proteins are also involved in the coating process. Surfactant recycling occurs through the endocytosis of small vesicles. Alterations in surfactant metabolism (Panel B) may occur at any of these steps. The exact pathophysiology of surfactant metabolism in ARDS has not been fully established, but it is likely to consist of both the destruction and the structural alteration of surfactant lipids and protein caused by the inflammatory milieu of the injured air space. In addition, synthesis and recycling of surfactant are likely to be reduced and its function impaired by the accumulation of proteinaceous material within the alveolus. TNF denotes tumor necrosis factor.
The small amount of protein in surfactant has important roles in both enhancing the properties that lower the surface tension and defending the lungs against infectious pathogens. The two hydrophobic proteins, surfactant proteins B and C, appear to be vital in normal animals and humans. Both proteins greatly enhance the spread of phospholipids in the lung. In animals with deletions in the gene encoding surfactant protein B (SP-B) and neonates with rare SP-B mutations, severe and irreversible respiratory failure develops. Interestingly, animals in which the gene encoding surfactant protein C (SP-C) has been "knocked out" do not initially have respiratory problems, but emphysema and pneumonitis develop in these animals in adulthood. The hydrophilic surfactant proteins, surfactant proteins A and D, are members of the collectin family, with established roles in the regulation of the innate immune system and in host defense.
Several studies have reported both absolute reductions in surfactant concentrations and functional alterations in surfactant composition in ARDS.4 Samples of bronchoalveolar-lavage fluid from patients with ARDS have lower concentrations of DPPC, phosphatidylglycerol, and surfactant proteins than samples from healthy persons. Surfactant from these patients also has an altered chemical composition, with reduced surface-tension–lowering properties ex vivo. In addition, a reduction of surfactant activity on exposure to bronchoalveolar-lavage samples from patients with acute lung injury has been reported. The mechanisms causing these changes are likely to involve alterations in the whole surfactant cycle, including synthesis, release, membrane incorporation, and recycling (see Figure). The highly inflammatory alveolar environment may damage and inactivate surfactant, and the proteinaceous alveolar exudate may compete with surfactant for incorporation into the air–fluid interface. Alveolar flooding and the increased permeability of the epithelial–endothelial barrier will also dilute surfactant, some of which may be lost into the circulation.
Surfactant-replacement therapy in ARDS is therefore both a biologically plausible hypothesis and a therapeutic possibility, as demonstrated by successful trials in neonates. Why has it not been successful in adults? The most obvious explanation is that the surfactant hypothesis as applied to ARDS is simply wrong. Most patients with acute lung injury die of multiorgan failure and sepsis, not of isolated respiratory failure.2 However, the Acute Respiratory Distress Syndrome Network (ARDSNet) trial proved that changes in ventilator management alone can alter outcome.5 In addition, the possibility that surfactant loss may be a part of ventilator-induced lung injury strengthens arguments in favor of exogenous replacement.
Other explanations of the failure of this approach are of a technical nature.3 The replacement surfactants used in the studies differ from human surfactant in composition. All lack components of human surfactant, including some or all of the proteins — a difference that has unknown effects on clinical efficacy. The concentration of surfactant that is achieved in the damaged alveoli is also unknown. Preferential deposition in healthy lung units, inactivation in damaged alveoli, and variable delivery systems may all contribute to failure in these trials. Earlier initiation of surfactant replacement might be more beneficial, but patients receive therapy only when the lung injury is established and relatively advanced. Patients with ARDS are also a heterogenous group. The response to treatment of direct lung injury may differ from that in patients with indirect lung injury — an issue raised by the current study. In addition, surfactant might improve functional recovery from acute lung injury without influencing short-term mortality.
The idea of delivering local therapy to the injured lung remains immensely attractive. Exogenous surfactant therapy has still not fulfilled its theoretical promise, but recombinant technology will allow more complex preparations to be developed, and further clinical trials are being conducted. As they say at halftime in the big match, "It's not over yet."
Source Information
From the University Department of Surgical Sciences and the Department of Anaesthesia, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom.
References
1. Anzueto A, Baughman RP, Guntupalli KK, et al. Aerosolized surfactant in adults with sepsis-induced acute respiratory distress syndrome. N Engl J Med 1996;334:1417-1422.[Abstract/Full Text]
2. Wyncoll DLA, Evans TW. Acute respiratory distress syndrome. Lancet 1999;354:497-501.[CrossRef][ISI][Medline]
3. Robertson B, Halliday HL. Principles of surfactant replacement. Biochim Biophys Acta 1998;1408:346-361.[ISI][Medline]
4. Haitsma JJ, Papadakos PJ, Lachmann B. Surfactant therapy for acute lung injury/acute respiratory distress syndrome. Curr Opin Crit Care 2004;10:18-22.[Medline]
5. The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000;342:1301-1308.[Abstract/Full Text] |
