Effect of exogenous surfactant (calfactant) in pediatric acute lung injury

JAMA 2005;293:470-476.

Introduction

Surfactant dysfunction plays an important role in the Acute Respiratory Distress Syndrome (ARDS). Analogous to surfactant replacement therapy in neonates with IRDS, several trials have investigated the effects of synthetic or recombinant surfactant in adults with ARDS or Acute Lung Injury (ALI). The outcome of these studies has been disappointing. One of the reasons for this failure might be the composition of the surfactant. A bovine lung surfactant containing apoprotein surfactant-specific protein B: SP-B (calfactant) was used in preliminary trials in children with promising results. The aim of this study was to investigate whether intratracheal instillation of calfactant in children with ARDS or ALI shortens the duration of respiratory failure.

Study

The study enrolled a total number of 152 patients aged 1 week to 21 years. Entry criteria included respiratory failure with bilateral parenchymal lung disease leading to mechanical ventilation and an oxygenation index (OI) > 7. Exclusion criteria included prematurity and an underlying illness that might influence the course of respiratory failure. The study group received an intratracheal instillation of 2 doses of 80 ml/m2 calfactant. The control group received an equivalent amount of air placebo. A second dose was given 12 hours later if OI was still > 7. Strict ventilator guidelines were followed for all patients.

The primary outcome measure was the number of ventilator-free days in the 28 days following study entry. Death or the need for extracorporeal membrane oxygenation was considered equal to no ventilator free days. Additional outcome measures included length of stay (LOS) and hospital charges, failure of conventional mechanical ventilation leading to NO-therapy, high-frequency oscillatory ventilation or extracorporeal membrane oxygenation and duration of supplemental oxygen therapy. Complications were monitored including hypotension and deterioration in oxygenation.

There was no significant difference in the primary outcome measure. However there was a significantly higher mortality rate in the placebo group (27/75 versus 15/77) and a significantly lower OI in the calfactant group. There was no difference in the LOS. More patients in the placebo group failed to respond to conventional mechanical ventilation. The main immediate complications were hypotension responding to volume suppletion and transient hypoxia.

Discussion

This study is a multicentre randomized controlled trial. Randomisation and blinding procedures appear to be adequate. Follow-up was complete. Analysis was on an intention-to-treat basis and both groups were further treated equally. Although there was no difference in the total number of ventilator-free days, mortality was significantly higher in the placebo group with a RR of 1.85 (1.07 - 3.19). The NNT to prevent one additional death with calfactant was 5.9. Unfortunately, baseline characteristics showed a significantly higher number of immunocompromised children in the placebo group, which may have contributed to the higher mortality rate. When the authors entered the immunocompromised state in a logistic regression model the p-value for the difference between the calfactant and the placebo group increased to 0.07. Adverse effects of calfactant therapy appear to be mild. We agree with the authors that calfactant is a serious option in the treatment of non-immunocompromised children with ARDS or ALI.

N.Meijer, Fellow Kinder Intensive Care
J.G. van der Hoeven, Internist-Intensivist