Pediatric calfactant in acute respiratory distress syndrome trial.

RATIONALE: Our previous studies in children with acute lung injury/acute respiratory distress syndrome demonstrated improved outcomes with exogenous surfactant (calfactant) administration. Sample sizes in those studies were small, however, and the subject populations heterogeneous, thus making recommendations tenuous. OBJECTIVE: To investigate the efficacy of surfactant administration in a larger, more homogenous population of children with lung injury/acute respiratory distress syndrome due to direct lung injury. DESIGN AND SETTING: Masked, randomized, placebo-controlled trial in 24 children's hospitals in six different countries. PATIENTS AND METHODS: Children 37 weeks postconception to 18 years old with lung injury/acute respiratory distress syndrome due to direct lung injury were randomized to receive up to three doses of 30 mg/cm height of surfactant (calfactant) versus placebo (air) within 48 hours of intubation and initiation of mechanical ventilation. The primary outcome was mortality at 90 days. Ventilator-free days, changes in oxygenation, and adverse events were also assessed. RESULTS: The study was stopped at the sponsor's request after the second interim analysis for presumed futility. A total of 110 subjects were enrolled, with consent withdrawn from one whose data are unavailable. There were no significant differences between groups except in hospital-free days (10.4 ± 7.8 placebo vs 6.4 ± 7.8 surfactant; p = 0.01). Overall 90-day mortality was 11% (seven surfactant, five placebo). No immediate improvement in oxygenation was associated with surfactant administration. CONCLUSIONS: Surfactant did not improve outcomes relative to placebo in this trial of children with direct lung injury/acute respiratory distress syndrome. Differences in concentration of the surfactant, failure to recruit the lung during surfactant administration, or using two rather than four position changes during administration are possible explanations for the difference from previous studies. Exogenous surfactant cannot be recommended at this time for children with direct lung injury/acute respiratory distress syndrome.

The relationship of fluid administration to outcome in the pediatric calfactant in acute respiratory distress syndrome trial.

OBJECTIVES: Adult studies have demonstrated the relationship between fluid overload and poor outcomes in acute lung injury/acute respiratory distress syndrome. The approach of pediatric intensivists to fluid management in acute lung injury/acute respiratory distress syndrome and its effect on outcomes is less clear. In a post hoc analysis of our Calfactant in Acute Respiratory Distress Syndrome trial, we examined the relationship of fluid balance to in-hospital outcomes in subjects with acute lung injury/acute respiratory distress syndrome. DESIGN: Calfactant in Acute Respiratory Distress Syndrome was a masked randomized controlled trial of calfactant surfactant versus placebo in pediatric patients with acute lung injury/acute respiratory distress syndrome due to direct lung injury. Caregivers were encouraged to follow a conservative fluid management guideline based on the adult Fluid and Catheter Treatment Trial. Daily fluid balance was collected for the first 7 days after trial enrollment and correlated with clinical outcomes. PATIENTS AND SETTING: Children admitted to PICUs with acute lung injury/acute respiratory distress syndrome from 24 children's hospitals in six different countries. INTERVENTION: Post hoc analysis of daily fluid balance in subjects from the Pediatric Calfactant in Acute Respiratory Distress Syndrome trial. MEASUREMENTS AND MAIN RESULTS: Despite the conservative fluid guideline, fluid management was more consistent with a "liberal" approach. On average, study subjects accumulated 1.96 ± 4.2 L/m over the first 7 days of the trial. Subjects who died accumulated on average 8.7 ± 9.5 L/m versus 1.2 ± 2.4 L/m in survivors. Increasing fluid accumulation was associated with fewer ventilator-free days and worsening oxygenation. Multivariable regression models that included age, gender, Pediatric Risk of Mortality score, initial oxygen saturation index and PaO2/FIO2 ratio, injury category, and treatment arm failed to account for the differences in fluid management. CONCLUSIONS: Pediatric intensivists generally follow a "liberal" approach to fluid management in children with acute lung injury/acute respiratory distress syndrome. Illness severity or oxygenation disturbance did not explain differences in fluid accumulation but such accumulation was associated with worsening oxygenation, a longer ventilator course, and increased mortality. A more conservative approach to fluid management may improve outcomes in children with acute lung injury/acute respiratory distress syndrome.

The Adult Calfactant in Acute Respiratory Distress Syndrome Trial.

BACKGROUND: Surfactant has been shown to be dysfunctional in ARDS, and exogenous surfactant has proven effective in many forms of neonatal and pediatric acute lung injury (ALI). In view of the positive results of our studies in children along with evidence that surfactant-associated protein B containing pharmaceutical surfactants might be more effective, we designed a multiinstitutional, randomized, controlled, and masked trial of calfactant, a calf lung surfactant, in adults and children with ALI/ARDS due to direct lung injury. METHODS: Adult subjects within 48 h of initiation of mechanical ventilation for direct ARDS were randomized to receive up to three interventions with instilled calfactant vs air placebo. The primary outcome was 90-day all-cause mortality. RESULTS: Three hundred seventeen subjects were enrolled, 308 of whom could be evaluated. There were no significant baseline differences between groups. Calfactant administration was not associated with improved survival, lengths of stay, or oxygenation. Calfactant instillation was frequently associated with transient hypoxia and hypotension. The study was stopped at the first interim analysis at the sponsor's request. CONCLUSIONS: Administration of calfactant was not associated with improved oxygenation or longer-term benefits relative to placebo in this randomized, controlled, and masked trial. At present, exogenous surfactant cannot be recommended for routine clinical use in ARDS. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00682500; URL: www.clinicaltrials.gov.