Surfactant depletion and dysfunction play an important role in the pathophysiology of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Reports have detailed impairments in surfactant activity related both to dilutional effects from leaking alveolar proteins and effects from chemical alterations by phospholipases and reactive oxygen species. Additionally, the content of large surfactant aggregates and surfactant proteins A and B, necessary to maintain alveolar integrity, are reduced secondary to problems with processing and metabolism.
As such, the notion that repletion of surfactant could improve outcomes in adult and pediatric patients with ARDS has been studied in a number of investigations. The authors of a trial published in the September issue of Pediatric Critical Care Medicine detail some of these works, explaining that most successes have been in small trials whose results were not replicated in larger ones.
The authors conducted a masked, randomized, placebo-controlled multi-institutional trial, which was coupled to an adult study using the same protocols. Children with a diagnosis of ALI/ARDS, based on the American-European Consensus Conference definition, were recruited within 48 hours of the initiation of mechanical ventilation. Subjects’ ages ranged from 37 weeks postconception to 18 years. Because successful use of surfactant in the small trials appeared predominately in cases caused by direct lung injury (as opposed to remote sources like pancreatitis or sepsis), only those patients with alveolar injury were recruited to maintain homogeneity. Once subjects were screened, the authors randomized them into two groups: those receiving surfactant and those receiving placebo. The subjects with worse gas exchange were independently randomized to assure an even distribution of severely ill patients in both groups. The primary outcome was all-cause mortality at 90 days. Secondary measure outcomes included ventilator-free days at 28 days, ICU and hospital lengths of stay, changes in oxygenation, and adverse events.
One hundred ten pediatric patients underwent randomization: 56 to the surfactant group and 53 in the placebo group (one patient was randomized but not treated). Both groups were similar in demographics and degrees of illness. However, during the second interim analysis, the study was stopped secondary to presumed futility. Although the surfactant group had fewer hospital days, the primary outcome of all-cause mortality was similar between groups, as were all other secondary outcomes. Interestingly, no improvement was seen in oxygenation after surfactant administration, which has consistently been reported in other trials. Adverse events were few between the groups, and all subjects recovered without sequelae.
The authors cited a number of reasons for the lack of improvement in outcomes. For example, the lack of a recruitment maneuver and the employment of only two position changes during the instillation process were differences between this study and smaller ones that were more successful in demonstrating a positive effect. Additionally, the surfactant used in this trial was more concentrated than that used in earlier pediatric trials, because of concern of the liquid load on the lung. All of these changes in protocols from previous studies were conceded to maintain equivalency with the adult portion of this trial.
While these differences in instillation and drug concentration may play a role in the absence of a positive effect, the authors also cite a potentially more important reason. Although these patients were not as sick as those in their previous study, the low mortality rate (11%) in this study compared to their previous one (27%) suggests that better fluid and ventilator management may play a important role.
Regardless of the reason, this study demonstrates that there is no benefit to using surfactant in pediatric patients with ALI/ARDS resulting from direct lung injury.
This Concise Critical Appraisal is authored by SCCM member Daniel E. Sloniewsky, MD. Each installment highlights journal articles most relevant to the critical care practitioner. Daniel Sloniewsky is an associate professor in the Department of Pediatrics at the Stony Brook Long Island Children’s Hospital in Stony Brook, NY, where he is board certified in pediatrics and pediatric critical care. He completed his fellowship training at Children’s Memorial Hospital and Northwestern University in Chicago. His major interests are in acute pediatric pulmonary disease, transfusion medicine and ethics. He is also actively involved in resident education, Pediatric Advanced Life Support and Pediatric Fundamental Critical Care Support instruction.