Exogenous pulmonary surfactant for the treatment of adult patients with acute respiratory distress syndrome: results of a meta-analysis

Acute respiratory distress syndrome (ARDS) is a common cause of respiratory failure in the intensive care unit. Patients with ARDS exhibit an intense inflammatory reaction centered in the lung parenchyma, resulting in alveolar flooding and collapse, in reduced lung compliance, in increased work of breathing, and in severe impairments in gas exchange [1‐4]. Patients with ARDS have an inhospital mortality rate ranging from 34% to 60% [5]. Treatment of patients with ARDS is largely supportive, and includes mechanical ventilation with low tidal volumes [6], positive end expiratory pressure to open collapsed alveoli [7], supplemental oxygen, and supportive care of other organ system failures. Given the high mortality rate of patients with ARDS, other therapies are clearly needed.

Administration of exogenous pulmonary surfactant is an adjunctive therapy that may help adult patients with ARDS. Pulmonary surfactant is produced by type II alveolar cells and is composed of two major fractions: phospholipids (90%) and surfactant-specific proteins (10%). Surfactant decreases alveolar surface tension, thereby preventing alveolar collapse and allowing efficient gas exchange at low transpulmonary pressures. Furthermore, surfactant has important roles in host immune defense, through both specific and nonspecific mechanisms [8].

Patients with ARDS show injury to the alveolar epithelial barrier with consequent surfactant dysfunction. Indeed, surfactant recovered from bronchoalveolar lavage fluid from ARDS patients has alterations of the phospholipid and fatty acid profile, has decreased levels of surfactant-specific proteins, and has impaired surface-tension-lowering properties. Causes of this impairment include the inhibition of surfactant function by protein-rich edema fluid, by surfactant lipid peroxidation, and by surfactant protein degradation [1, 9]. Given these abnormalities, administration of exogenous pulmonary surfactant has been considered a possible treatment option in adult patients with ARDS [8].

The purpose of this study was to perform a systematic review and meta-analysis of exogenous surfactant administration to assess whether this therapy, as currently administered, may be useful in adult patients with ARDS.

Adult patients with ARDS exhibit a reduction in the amount and function of surface-active material recovered by bronchoalveolar lavage. In addition, the phospholipid, fatty acid, and apoprotein profiles of pulmonary surfactant are altered [1]. It would therefore seem sensible that exogenous pulmonary surfactant would be a useful therapy in the treatment of ARDS. Our meta-analysis of six randomized controlled trials, however, demonstrated little utility of the therapy [16‐20]. There was no overall improvement in mortality (OR 0.97; 95% CI 0.73, 1.30). Furthermore, subgroup analysis of preparations with surfactant proteins in addition to phospholipids did not demonstrate improved outcomes (OR 0.87; 95% CI 0.48, 1.58). In three of the studies we were able to assess the impact of surfactant on oxygenation (for instance the PaO₂:FiO₂ ratio 24 hours following surfactant administration). Although there was a trend to improved oxygenation, this did not reach statistical significance (mean change 13.18 mmHg, standard error 8.23 mmHg; 95% CI -2.95, 29.32).

Our search for all published randomized controlled trials was thorough. Each study was assessed for quality and was chosen only if they were similar with respect to study participants and outcome measure. Mortality was chosen as the primary outcome given its importance in clinical practice. Unlike the most recent published meta-analysis [28], we attempted to assess oxygenation (PaO₂:FiO₂ ratio), the number of ventilation-free days, and the mean duration of ventilation. Unfortunately, there were limited data available for analysis of the change in oxygenation and insufficient data for assessment of ventilation characteristics. It is possible that we may have missed some published and unpublished articles.

The quality of the studies varied in our meta-analysis. Using the Jadad scoring system [10], four of the studies were of high quality (Jadad score 4 or 5) [16, 17, 20] but two studies were not (Jadad score 2) [18, 19] (Table 4). Of the latter two studies, one was a phase I/II prospective, randomized trial while the other was open-labeled. Notably these two studies had the lowest OR for mortality, and their exclusion, which would favor the null hypothesis, would not have changed our results significantly.

A limitation of our analysis is the many differences among the various studies. First, different types of surfactant were used. Two of the studies used synthetic surfactant (Exosurf) containing no surfactant protein [16, 17]. These studies have been criticized given the emerging data on the importance of surfactant proteins in the proper functioning of surfactant [29, 30]. It has been shown that surfactant-associated protein concentrations are decreased in bronchoalveolar lavage samples obtained from patients with ARDS compared with samples from control subjects [3]. Four surfactant proteins have been previously identified (SP-A, SP-B, SP-C, and SP-D). SP-B and SP-C are hydrophobic proteins that enhance the lowering of surface tension [8]. In the three studies using protein-based surfactant, two were recombinant preparations incorporating SP-C [19, 20] while the other was a bovine extract with both SP-B and SP-C [18]. SP-A and SP-D are hydrophilic proteins whose role appears to center around host defense [8]. None of the trials in our analysis, however, used surfactant containing SP-A or SP-D. It is possible that the presence of these proteins could increase the effectiveness of therapy.

Second, the different delivery methods used may have resulted in varying concentrations of surfactant reaching the damaged alveoli and altering the effectiveness of therapy. It has been shown that the relative rate of pulmonary deposition of surfactant is 4–5% using the aerosolization route [17, 29, 30]. In the article by Anzueto and colleagues [17] this would correspond to delivery of less than 5 mg/kg/day phospholipid, while other investigations have suggested that administration of 300 mg/kg/day may be required [30]. The ability of intratracheal administration, the method used by most of the studies in this meta-analysis, to effectively deliver of surfactant to the alveoli is unclear. Delivery of surfactant using the bronchoscopic route has been shown to be efficacious and safe, with initial studies showing improved oxygenation and a trend toward improved mortality [11‐15]. None of the trials using this method, however, met the inclusion criteria for our analysis. Nevertheless, bronchoscopic administration may be a potential promising path of future investigation.

Third, there were a variety of other differences between the studies including ventilation strategies and the time to surfactant administration. In this meta-analysis, three studies utilized the low tidal volume approach [19, 20] while one trial used traditional tidal volumes [18]. Two trials did not specify the ventilation strategy used [16, 17]. Most studies required administration of surfactant within 48 hours of the diagnosis of ARDS. One study allowed administration up to 72 hours after ARDS was diagnosed [20]. The timing of administration is an important issue as the response to early therapy versus delayed therapy may be significant [3].

Finally, the populations that were studied included patients with a wide variety of predisposing causes for ARDS. Patients with ARDS associated with indirect causes, for example sepsis, trauma, or pancreatitis, have a greater number of potentially fatal comorbidities than do patients with ARDS from direct causes such as aspiration or pneumonia [20]. Surfactant is unlikely to prevent nonpulmonary causes of death, and thus may only be effective in the subset of ARDS patients with direct lung injury. In a recent study of pediatric patients with acute lung injury, treatment with surfactant significantly improved oxygenation and survival in the subgroup of patients with direct acute lung injury, while having little effect on patients with indirect acute lung injury [31]. To date, studies focusing on the adult population with direct acute lung injury have not been reported.

Our results confirm and extend those of Adhikari and colleagues [28], who recently published a meta-analysis of a variety pharmacologic agents (for instance prostaglandin E, N-acetylcysteine, high-dose steroids, pulmonary surfactant, pentoxifylline) used in the treatment of ARDS and acute lung injury. Their review had significant differences compared with ours, however. First, five of the nine studies included in their review were abstracts, several of which did not include a placebo group. Second, they were only able to assess early mortality and did not include the change in the PaO₂:FiO₂ ratio. Finally, they did not perform subgroup analyses. Despite these methodologic differences, their results were consistent with ours in that exogenous pulmonary surfactant was found to have no significant effect on mortality (relative risk 0.93; 95% CI 0.77, 1.12).

We found in our meta-analysis that exogenous surfactant may improve oxygenation but did not improve mortality. Given the abnormalities of surfactant function found in patients with ARDS, the lack of effectiveness of exogenous surfactant is somewhat surprising. One potential explanation is that patients with ARDS usually die of multi-organ system failure from their underlying disease process (for example sepsis) rather than from respiratory failure per se. As such, treatment of the pulmonary abnormalities may not affect mortality substantially. Evaluation of surfactant treatment of patients with direct lung injury may clarify this issue. Another potential explanation is that the proper 'surfactant recipe' has not yet been found. That is, there may be a dose, formulation, and delivery strategy of surfactant that could be effective in patients in ARDS, potentially when combined with other therapies such as lung protective ventilation [6], high-frequency ventilation [32], prone positioning [33], or extracorporeal membrane oxygenation [34]. Future studies may eventually discover such an approach, but exogenous surfactant cannot currently be considered an effective adjunctive therapy in ARDS.