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Exogenous Surfactant Does Not Improve Outcomes in Adults with Acute Lung Injury or ARDS
Abstract & Commentary
By David J. Pierson, MD, Editor, Professor, Pulmonary and Critical Care Medicine, Harborview Medical Center, University of Washington, Seattle, is Editor for Critical Care Alert.
Synopsis: This international multicenter clinical trial of bolus administration of porcine-derived exogenous surfactant to patients with acute lung injury or acute respiratory distress syndrome was stopped early because of a trend toward worse survival in the group that received the active treatment.
Source: Kesecioglu J, et al. Exogenous natural surfactant for treatment of acute lung injury and the acute respiratory distress syndrome. Am J Respir Crit Care Med 2009;180:989-994.
This large-scale clinical trial of exogenous surfactant administration in adult patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) used internationally accepted diagnostic criteria and the ARDS Net lung-protective ventilation protocol1 in all patients. In patients entered soon after diagnostic criteria were first met, the study sought to determine whether large-bolus instillation of the bovine-derived surfactant HL 10 (up to 300 mL into each lung at time 0 and again after 12 and 36 hours), in addition to conventional management, would improve survival at 28 and 180 days. It also investigated complications such as worsened hypoxemia and hypotension in association with administering the agent. Although randomized, the study could not be blinded.
The plan was to study 1000 patients, in 67 participating medical centers in 11 European countries and Canada. However, as a result of a planned interim analysis once 300 patients had been entered, the study was stopped early because of a trend toward higher mortality in the surfactant group. In this article, Kesecioglu et al report the results in the 418 patients (208 in the surfactant group, 210 in the control group) who completed the trial before it was halted.
The patients (mean age, 57 years; 65% men) had sepsis (35%), pneumonia/shock/other (52%), and aspiration pneumonia/trauma (13%) as underlying predispositions to ALI-ARDS, with no significant differences between the 78% who had ARDS and the 22% who had ALI at study entry other than in the oxygenation criteria. Mortality at 28 days was 24.5% in the usual care group vs 28.8% in the surfactant group (odds ratio for death by day 28, 0.75; 95% confidence interval, 0.48-1.18; P = 0.22). The most common adverse events temporally related to surfactant administration were reductions in oxygen saturation to < 88% (which occurred in 52% of the surfactant group vs 25% of the usual care group) and hypotension (to mean arterial pressure < 60 mm Hg, in 34% and 17%, respectively). Thus, in this study, instillation of a large bolus of the exogenous natural porcine surfactant HL 10 into patients with ALI or ARDS did not improve outcome and showed a trend toward increased mortality and adverse effects.
Surfactant is depleted and/or dysfunctional in severe acute respiratory failure. In neonates with respiratory distress syndrome, and also in children with ALI-ARDS, surfactant instillation has been shown to improve both respiratory function and clinical outcomes. However, synthetic surfactant preparations have been ineffective in two previous clinical trials in adult patients with ALI-ARDS.2,3 Although a smaller trial using bovine surfactant suggested that its administration was safe and associated with a trend toward better survival,4 the current study found no such trend, and its results certainly dampen clinical enthusiasm for the use of natural surfactant in managing patients with this form of acute respiratory failure.
The overall mortality among the patients entered into this trial (25%-29%) is comparable to that observed in other large-scale clinical trials in ALI-ARDS during the last decade. Recent trials by the ARDS Network, which have employed the low-tidal-volume, lung-protective ventilation regimen used in its original trial,1 have observed survival rates generally similar to those seen in the current study. This represents a major improvement over the outcomes for ALI-ARDS of 25-30 years ago, as has been documented in numerous studies. What accounts for this marked improvement is still unknown, but it is not a matter of which ventilator mode is used (volume-targeted assist-control vs pressure-control, etc.), how much PEEP is used, recruitment maneuvers, or the addition of prone positioning, inhaled nitric oxide, or high-frequency oscillatory ventilation to the management regimen. While those interventions improve oxygenation in many patients — as does the use of larger tidal volumes and higher ventilating pressures — they have not been shown to benefit patient-centered outcomes such as survival and length of stay. In the present study, the intervention (surfactant instillation) actually worsened oxygenation, and no suggestion of clinically relevant benefit was found.