Question

• In the pediatric population with Acute Lung Injury (ALI), is the use of surfactant therapy beneficial?

Clinical Bottom Lines

1. The use of surfactant did NOT lead to a significant difference in the duration of respiratory failure as measured by duration of conventional mechanical ventilator therapy.
2. Although the study was underpowered for sub-group analysis, duration of mechanical ventilation was noted to be significantly shorter in infants younger than 12 months who received surfactant vs placebo, p=0.01.
3. Short term oxygenation as measured by oxygenation index significantly improved with use of two doses of surfactant (Calfactant), p=0.02. Improvement was measured over the 24 hour period after the second dose.
4. There was no significant difference in duration of oxygen therapy, hospital charges, hospital and PICU lengths of stay between the surfactant therapy group and placebo.
5. Mortality rate was significantly greater in the placebo group (RR 1.9 and 95% CI 1.1-3.2). The ARR is 17%, and NNT=6.
6. Conventional mechanical failure occurred more in the placebo group compared to the surfactant group. (p=0.02 ).

Summary of Key Evidence

1. This was a multicentered (21 tertiary care PICUs in the U.S.) conducted as a randomized, double blinded, placebo controlled trial.¹
2. 152 patients were enrolled with inclusion criteria of: age (1 week to 21 years old), respiratory failure due to radiographically evident bilateral parenchymal lung disease, enrollment was initially within 24 hours of initiating mechanical ventilation for the first 50 patients and subsequently within 48 hours of initiating mechanical ventilation, and an oxygnenation index higher than 7.
3. Exclusion criteria for the study were: prematurity (corrected gestation age < 37 weeks); status asthmaticus; chronic lung disease defined by home oxygen use or diuretic use; brain death, do not resuscitate orders, ongoing cardiopulmonary resuscitation, or limitation of life support; significant airway disease that may delay extubation; uncorrected congenital heart disease, pre-existing myocardial dysfunction, or cardiogenic pulmonary edema; head injury with Glasgow Coma Scale of less than 8.
4. Study Design: The experimental group received 80ml/m2 calfactant via intra-tracheal instillation. A second dose was given in both groups if the oxygenation index was greater than 7 at 12 hours after the first dose. The control group received an equal volume of air placebo. Mechanical ventilation parameters were given and the use of other surfactants were prohibited.
5. Validity of the study: Patients in the experimental and the placebo groups were demographically similar and matched for co-existing co-morbidities. The patients were appropriately randomized and stratified to balance the severity for lung injury between each group at study entry. Patients, nurses and clinicians remained blinded throughout the study. Follow up was complete and all patients were included in the final analysis for outcomes. Patients were analyzed in their original groups of randomization (no cross over occurred). Adherence of ventilator management was equal in both groups. All other aspects of care was determined by the clinical team.
6. Primary outcome measured at 28 days was the number of ventilator free days as a measure of duration of respiratory failure. Secondary outcomes were hospital length of stay, charges, duration of supplemental oxygen, adverse events and failure of conventional ventilation.

Additional Comments

• Although overall mortality was higher in the placebo group than the surfactant group, it is concerning what effect there was of having 5 more imunocompromised patients in the placebo group than the treatment group. The authors noted this difference as being statistically insignificant. The odds ratio and confidence interval of treatment effect on mortality adjusted for immunocompromised state was statistically insignificant (p=0.07, C.I. 0.93-4.79 for OI of 2.11. The study calculated mortality as still being significantly lower in immunocompetent patients receiving surfactant vs. placebo. However, the study was not powered to detect sub-group effects.
• There was no a priori definition of when conventional mechanical ventilation was considered a failure. This was left to the individual clinical care team.
• Significance of acute improvement in oxygenation index difficult to interpret in terms of long term outcome measured in study. In any case, the study not powered to make this association/interpretation.
• The study was underpowered:
  • Not powered as planned for overall study's primary outcome (ventilator free days). A priori calculation for power required 274 patients and only 152 were enrolled.
  • Not powered to make strata comparisons between placebo and surfactant group. For example, sub-group analysis by the authors indicated infants younger than 12 months in the placebo group had even higher mortality rates (ARR 33%, CI (95%) 1.2-22.8 but the study was underpowered to conduct reliable sub-group analysis.
• The differences in mechanisms of acute lung injury (direct lung injury e.g. pneumonia, versus indirect e.g. sepsis) may or may not affect responsiveness to surfactant therapy by improvement in oxygenation and ventilation. However, study was not designed to draw out these differences or to define possible populations more likely to respond to surfactant therapy during acute lung injury.
• A cost analysis was not done by the study, thereby limiting considering cost vs harm/benefit.
• Surfactant (calfactant) use was more likely to cause acute side effects of hypotension (p=0.005), and transient hypoxia (p=0.008) than compared to the placebo group. Although, these complications did not cause removal of patients from the study, the NNH (number needed to harm) is 11. These complications may limit use in certain pathophysiological states such as sepsis.
  

Citation

1. Willson DF, Thomas NJ, Markovitz BP, et al.; Pediatric Acute Lung Injury and Sepsis Investigators. Effect of Exogenous Surfactant (Calfactant) in Pediatric Acute Lung Injury: A Randomized Controlled Trial. JAMA 2005;293:470-6.

CAT Author: Aditi Dave, MD

CAT Appraisers: John Frohna, MD

Date appraised: September 14, 2005