- 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
- 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
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