A sustained inflation at birth of an asphyxiated lamb which lasts 30 seconds leads to much more rapid restoration of heart rate and blood pressure than either conventional ventilation or a series of shorter sustained inflations of 5 seconds each. This new study from the same group (Sobotka KS, et al. Single Sustained Inflation followed by Ventilation Leads to Rapid Cardiorespiratory Recovery but Causes Cerebral Vascular Leakage in Asphyxiated Near-Term Lambs. PLoS One. 2016;11(1):e0146574) shows that cardiac contractility, carotid artery flow and cerebral oxygen delivery also increase much more rapidly.
But, wait a minute, is that necessarily a good thing? What is important is the eventual re-establishment of a stable circulation, and a reduction in cerebral injury, and injury to other organs. One of the reasons we have switched to room air resuscitation (at least for full term infants) is that re-oxygenation injury is reduced compared to 100% oxygen resuscitation, maybe increasing cerebral perfusion and oxygen delivery very quickly might also have some harmful effects.
In this new study the authors also performed brain histopathology of the lambs after resuscitation, mostly looking at how many blood vessels in each of 3 sections of the brain were surrounded by extravasated serum. There were significantly more disrupted blood vessels and extravasations in the sub-cortical white matter of the single prolonged inflation lambs than the other 2 groups, and slightly more in the gray matter and the periventricular white matter also. Exactly why this occurs, what the potential impacts are and whether it might also occur in babies exposed to different kinds of sustained inflations is unknown, but will need to be investigated.
Two fairly recent randomized trials have concentrated on pulmonary outcomes:
In the first, nearly 300 infants from 25 to 29 weeks gestation were randomized, Lista G, et al. Sustained Lung Inflation at Birth for Preterm Infants: A Randomized Clinical Trial. Pediatrics. 2015;135(2):e457-e64. They either were placed on CPAP, or had a sustained lung inflation (25 cmH2O for 5 seconds) followed by CPAP. The SLI group were more likely to avoid mechanical ventilation during the first 72 hours of life, but the number ever intubated, the proportion who developed BPD and survival were not different. As the babies were not necessarily asphyxiated, this was really a trial of SLI as a lung protective strategy, which did not really show any benefit; other complications of prematurity, including IVH and PVL, were not different between groups.
The second study enrolled nearly 200 infants of 34 to 36 weeks gestation, Mercadante D, et al. Sustained lung inflation in late preterm infants: a randomized controlled trial. J Perinatol. 2016;36(6):443-7. They described the intervention as follows :
after oropharyngeal and nasal suctioning, a prophylactic pressure-controlled (25 cmH2O) inflation was sustained for 15 s using a neonatal mask and a T-piece ventilator, followed by the delivery of 5 cmH2O CPAP. In the following 6 to 10 s, CPAP was discontinued in the absence of signs of inadequate respiratory effort (that is, apnea or gasping) or heart rate 4100 beats per min (b.p.m.). In the presence of signs of inadequate respiratory effort and/or whenever the heart rate was between 60 and 100 b.p.m. despite CPAP, a SLI maneuver with the same parameters was repeated. If the heart rate was <100 b.p.m. after the second SLI maneuver, the infant was resuscitated according to the recommendations of the American Academy of Pediatrics (AAP).
This study showed no benefit of the procedure, and 3 babies in the SLI group, but none of the controls, developed a pneumothorax.
It seems to me we should be being very careful with this intervention, and I say this as someone who has done it intermittently for many years. I think I’ve mentioned before on this blog that Anthony Milner showed years ago in depressed full-term babies who were intubated before their first breath, that a prolonged (5 seconds) slow-rise inflation pressure, up to 30 cmH20 eliminated the apparent opening pressure of the lungs and led to rapid establishment of an FRC. My anecdotal experience is that sometimes when I take over ventilating a baby who the junior staff is having difficulty with, and I apply that kind of a long inflation, often the lungs will be easy to inflate, and then assisted ventilation is much easier, often with a recovery of other clinical signs.
I’m somewhat less convinced of the value of SLI as a lung-protective strategy for preterm infants, and certainly the clinical data so far do not support it. As a part of a resuscitative strategy for depressed babies, I think there is more promise; but it now looks like we will have to carefully examine potential neurologic compromise.
Neonatal Research 
What do you think of this?
Sustained versus intermittent lung inflation for resuscitation of preterm infants: a randomized controlled trial. El-Chimi MS et al. J Matern Fetal Neonatal Med. (2016).
Large Animal Studies of Birth Transition – meaning is in the details.
Hi Keith, I just came across this blog post and you raise some important points on supporting the lung at birth. There is no doubt we should look beyond the lung with regards to benefits and risks of sustained inflations, and indeed any other respiratory support approach.
The study of Sobotka et al is important and raises some concerns. But, caution must also be applied to how we interpret the clinical implications of animal studies. The details are very important, and I think you have not considered these with the rigour needed. Just like human studies, variables are multiple and often not anticipated in preterm large animal studies, especially maternal factors (unlike mice studies). The question is then whether a singular variable can be considered the principal contributor to the results found. Population size and design are thus important. The study of Sobotka et al highlights some of these issues. Six lambs were allocated to each intervention group. This approach is probably suitable for identifying biological processes but not necessarily for comparing interventions. Was 6/gp enough to adequately delineate the CNS injury outcomes being addressed in the aims? In this case we dont know as a power calculation is not provided. This is not a criticism of the authors as it is common practice in animal research (notice the high number of n=6-7/gp studies), although I dont agree with it.
Given that this is an asphyxia model (cord occlusion), and other factors (eg gender, maternal wellbeing etc) are not controlled, I would argue that n=6/gp is unlikely to be sufficient to account for variability and provide meaningful conclusions. There is some evidence to support this assertion. The groups are not similar (see Klingenberg ADC F&N 2012 which reports the populations) with regards to cord PaO2, lactate and pH before cord occlusion (which may also mean differential durations of asphyxia). The error spread on the Cardiovascular/CNS data (presented using SEM rather than SD, again a common practice in our field) suggests high population variability. Recently we reported cerebral blood flow (admittedly without CNS histology) in preterm lambs receiving one of three different SI vs PEEP-supported tidal ventilation (Am J Physiol Lung Cell Mol Physiol 2015; 309: L1138-L1149). We studied 12 lambs/gp (36 lambs receiving a SI), numbers powered to detect our intended oxygenation and compliance differences. We found no difference in cerebral blood flow (CBF) between the different strategies (although we already knew we would have needed larger numbers to do so). It is important to note that the role of a SI on the CNS was not the aim of our study but it serves to illustrate my argument that clinicians must consider all aspects of large animal research methodology. Despite these limitations, drawing conclusions from data involving 36 lambs is more robust than that of 6 lambs.
Finally, readers must question whether the preterm lamb (an established CVS/respiratory model) is appropriate to reflect brain injury patterns in human infants. Piglets have been widely used in asphyxial studies.
So, were does this leave us? I believe that the findings of Sobotka et al are correct. It is biologically plausible that asphyxia combined with a SI will result in the pattern of injury seen. But it is important I realise that this study alone can not convince me, especially as the findings sit well with my pre-held views regarding SI vs PEEP-supported tidal inflations. The findings may have been caused by many other effects. It would be interesting to see if these results can be replicated in larger studies that ensure variabilities are accounted for adequately.
As for SI in preterm infants, further lamb research is not needed just yet. A large clinical trial of SI in preterm infants is ongoing, we should await the results of this study. If a difference in any unexpected outcomes is identified, well designed animal studies will be essential to understand the reasons why.
More broadly, clinicians must ensure that those of us using large animals to understand birth transition are addressing the questions that need to be addressed in a way that clinicians can use the findings to the maximum potential.