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Aerosolized surfactant. Can we finally do away with intubation?

AllThingsNeonatal

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I have written about non-traditional methods of providing surfactant to newborns previously. The practice of intubating a preterm infant to administer surfactant and leaving the endotracheal tube in with a slow wean of ventilation is mostly a thing of the past (at least in my units). Strategies have evolved and have seen the development of the INSURE technique, LISA methods, use of an LMA to delivery surfactant and even simple deposition into the pharynx all with variable success.

The Holy Grail

To me at least, the Holy Grail of surfactant delivery has been aerosolization. A small non randomized study was done in by Finer et al in 2010 An open label, pilot study of Aerosurf® combined with nCPAP to prevent RDS in preterm neonates. This study noted a reduction in CPAP failure with nebulized surfactant but as a pilot was not large enough to move the needle. Since then the Cochrane group weighed in and declared that there was not enough evidence to support the practice. The CureNeb group anchored by Dr. Pillow though has now published a double blind RCT entitled Nebulised surfactant to reduce severity of respiratory distress: a blinded, parallel, randomized controlled trial. It certainly sounds interesting and might help determine if the needle has indeed moved.

The Study

Poractant alfa at 200 mg/kg was used in this study and delivered via aerosolization using a vibrating membrane called the eFlow. The authors chose to look at infants from 29 0/7 to 33 6/7 weeks at birth and stratified them into two groups of 29 0/7 to 31 6/7 and 32 0/7 to 33 6/7 weeks. They estimated a need for 70 babies based on an anticipated failure rate of 30% in the control group vs 5% in the treatment group. Unfortunately, due to several reasons the study was only able to recruit 64 babies for randomization before being stopped due to the recruitment issues. The design of the study included adequate blinding with a sham procedure and there were predefined “failure criteria” necessitating intubation at the outset of the study. These criteria are acceptable to me as they are similar enough to my own practice and were:

1. FiO2 >0.35 over more than 30 min OR FiO2 >0.45 at
anytime.
2. More than four apnoeas/hour OR two apnoeas requiring bag
and mask ventilation.
3. Two capillary blood gas samples with a pH <7.2 and partial pressure of carbon dioxide >65 mm Hg (or partial pressure
of carbon dioxide in arterial blood (PaCO2) >60 mm Hg if
arterial blood gas sample).
4. Intubation deemed necessary by the attending physician.

What did they find?

The primary outcome CPAP failure within 72 hours of birth was indeed different in the two groups.

  CPAP failure by 72 hours
CPAP + surfactant 11/32 (34%)
CPAP 22/32 (69%)

(RR (95% CI)=0.526 (0.292 to 0.950))

Clearly the event rates were quite off from what they expected in the power calculation but given that they found a difference as opposed to no difference at all the fact that they didn’t recruit the numbers they planned is of less importance.

However, what is interesting is when they looked at the planned analysis by stratification an interesting finding emerged.

Group 1 (29 0/7 to 31 6/7)

  CPAP failure by 72 hours
CPAP + surfactant 12/21 (57%)
CPAP 12/19 (63%)

(RR (95% CI)=0.860 (0.389 to 1.90))

Group 2 (32 0/7 to 33 6/7

  CPAP failure by 72 hours
CPAP + surfactant 1/11 (9%)
CPAP 10/13 (77%)

(RR (95% CI)=0.254 (0.089 to 0.727))

There were a number of secondary outcomes looked at as well which may be of interest to you but as the numbers here are quite small I will not comment other than to say there was no increased incidence of complications with surfactant administration in this fashion. Also for those who ultimately failed CPAP the time when they did so was quite delayed compared to CPAP alone. Age at intubation for nCPAP failure, hours 4.9 (2.7–10.6) 11.6 (9.0–31.1) 0.008*

What can we take from this?

I believe these results are encouraging even if the study is a small one. The message I take from this study is that aerosolization of surfactant delivers some amount of product to the lungs. Those with more significant RDS or smaller lungs (those in the 29 0/7 to 31 6/7 group) may not get enough surfactant to treat their RDS sufficiently to avoid intubation. Those with less significant RDS or a larger number of alveoli get “enough” of a dose delivered to the alveoli to make a difference and avoid intubation. It is worth stressing that there can be no specific comment about using this strategy in even more immature infants as they weren’t tested. If I had to guess though, I would expect no difference given the findings in the smaller group.
As a physician responsible for transport though I am interested in the potential benefits to those born in non-tertiary centres. Many centres lack individuals with the confidence and skill to regularly place endotracheal tubes. For these centres it may be that providing nebulized surfactant could delay the time to treatment failure, allowing more time for a trained transport team to arrive. Training of course would be needed in these centres on how to administer surfactant in this way but it is an interesting concept to consider. With a near tripling of the average time to treatment failure the extra hours on CPAP would be much appreciated when weather delays or difficulty securing air assets means long delays in transport team arrivals.

To be sure this isn’t the last study of this kind but it certainly is an interesting start and one that will no doubt produce questions that will help formulate the next study design.

 
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