A recent trial from Germany tried to answer the question of whether giving surfactant through a thin catheter while the baby was on CPAP would reduce “death or BPD” compared to intubation for surfactant. Kribs A, et al. Nonintubated Surfactant Application vs Conventional Therapy in Extremely Preterm Infants: A Randomized Clinical Trial. JAMA Pediatr. 2015;169(8):723-30. Infants of less than 28 weeks gestation, who were spontaneously breathing and needing more than 30% oxygen at between 10 and 120 minutes of age were enrolled, both groups received the same dose of Curosurf.
The main result of the trial is that to answer important questions like this in the early 21st century, you need big trials. This one was underpowered to find all except very large effects, with just over 100 babies per group. So although the primary outcome was improved in the LISA (less-invasive surfactant application) group, 67% surviving without BPD compared to 59% in the controls, this may have been due to chance, (p=0.2). If this was a real effect of the treatment, it would certainly be clinically worthwhile. The trial was high quality, just too small.
This brings me to another general point, the sample size was calculated on the estimate of a control rate of survival without BPD of 47% and an improvement to 69% with LISA. Apparently this was based on “data from an earlier feasibility study” but the reference they give was not to an earlier feasibility study, so I tried to find it, and the previous studies of LISA that I can find do not produce the figures they present. In any case using small pilot studies as a way of estimating a treatment effect is inherently unreliable, the smaller a study, the wider the confidence intervals around any result; sample sizes should be based on a realistic and clinically important estimate of an effect. William Tarnow-Mordi’s article in a recent Seminars in Fetal and Neonatal Medicine is a good place to read about some of these issues. For a trial of LISA if the expected control group outcome is around 50%, and increase in survival without BPD to 60% would be worthwhile, especially if there are no adverse consequences. To have an 80% chance of detecting such an effect you need around 400 per group, to have a 90% chance of doing so you need around 500 per group.
To return to the new trial, the secondary outcomes looked better in the LISA group, with less severe intraventricular hemorrhage, fewer intubations and fewer pneumothoraces. The main secondary outcome was pre-specified as survival without “major morbidity” which was BPD, severe IVH, cystic PVL, surgically treated retinopathy, or surgical NEC or perforation. That outcome was increased in the LISA group.
I would say the answer to the question in the title, is “not there yet” so far there seems to be no downside, none of the studies have shown an increase in any adverse outcome, but there is no clear evidence of benefit for BPD.
I am still concerned about performing a laryngoscopy for the procedure without premedication; laryngoscopy is very unpleasant, and is responsible for most of the adverse physiologic response seen during intubation. Apparently premedication was not routine in either group in this trial, which I think is very inappropriate. Once a baby has vascular access, there is no good reason for not premedicating prior to endotracheal intubation; finding an analgesia/sedation routine to use during LISA (or MIST if you prefer that acronym) is, I think, a priority.
I absolutely agree with all your comments. I’m just wondering if there is no better method to deliver surfactant than using a laryngoscope. There are some promising reports using a laryngeal mask, but I don’t know if this procedure is more pleassant for the babies. My feeling is that we should look for a more elegant and pleasant method to deliver surfactant. What about using a small video-laryngoscope? Just some thoughts ….