Author’s Response

We appreciate the comments offered by Choubey et al. We offer the following in reply.

Choubey et al stated that the requirement for surfactant in our study patients was much higher than described in the literature. That is incorrect. The reported incidence of 12.8% they cited refers to all NICU admissions, not only those with RDS. In our study population, which was limited to newborns with RDS requiring noninvasive respiratory support, the incidence of intubation for instilled surfactant in the usual care (control) group was actually lower than one might anticipate, on the basis of a clinical trial reported just before starting our study. The 50% incidence of intubation for instilled surfactant in our control group, at a mean gestational age of 33 weeks, is consistent with results reported in the CureNeb study, in which researchers found a 68% incidence of intubation for instilled surfactant in the control group of newborns with RDS, at a slightly earlier mean gestational age of 31 weeks.

As noted by Choubey et al, the primary outcome of our study was the need for intubation and instilled surfactant, as determined by the neonatologist. They concluded that this pragmatic approach would decrease generalizability. We disagree. By allowing NICUs to follow their own best practices, our study design increases, not decreases, the generalizability of our results. Indeed, the intended benefit of pragmatic trials is that they improve external validity, that is, applicability to the real world.

Choubey at al suggest that our study approach using aerosolized calfactant introduces a significantly higher cost without any reduction in relevant clinical outcomes. We disagree on both counts. The additional cost related to aerosolized calfactant would represent an extremely small portion of overall hospitalization costs for a preterm infant with RDS and would be partly offset by the reduced need for intubation and instilled surfactant. We also found that, among study infants with so-called “mild” RDS, those who received aerosolized calfactant weaned from respiratory support significantly faster than infants receiving usual care, suggesting additional cost savings. In regard to reducing relevant clinical outcomes, we strongly believe that a nearly 50% reduction in intubation, as shown in our study, is highly relevant to the clinical care of the fragile newborn infant.

Lastly, Choubey et al suggest that future trials of aerosolized surfactant could be focused on smaller preterm infants in an effort to reduce CLD among infants at the highest risk. Despite a relatively small sample size, the lack of benefit we found in infants born at 23 to 26 weeks’ gestation suggests otherwise. For a variety of reasons, drug delivery by aerosolization in nonintubated newborns is likely to be increasingly less effective with decreasing gestational age. Other alternatives to intubation that are both less invasive than intubation and still highly effective at delivering surfactant, such as supraglottic airway devices, carry significantly more promise for those infants at the highest risk for adverse pulmonary outcomes, namely those born before 27 weeks’ gestation.