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.
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
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
(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
(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
(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.
This post has the potential to be polarizing as sustained inflations while common as an approach after delivery in Europe has not been widely adopted in Canada and the United States. Some time ago I wrote about sustained inflations and a reader commented that I should wait for the results of the The Sustained Aeration for Infant Lungs (SAIL) trial before forming a final opinion on whether this is a good strategy or not. The previous blog post on this topic was Is It Time To Use Sustained Lung Inflation in NRP? and was followed by Is expired CO2 the key to making sustained inflation a standard in resuscitation? The first post concluded that there was a concerning trend towards more IVH in those who received sustained inflations (SI) while the second showed both a reduction in BPD and duration of mechanical ventilation with this approach. I suggested that maybe we were really onto something here and then I was asked to wait before coming to a conclusion until the SAIL trial was done. Well that day has come.
The SAIL trial
This trial led by Dr. H. Kirpalani and involving 18 NICUs in 9 countries was a big endeavour. The paper was just published and is entitled Effect of Sustained Inflations vs Intermittent Positive Pressure Ventilation on Bronchopulmonary Dysplasia or Death Among Extremely Preterm Infants The SAIL Randomized Clinical Trial. The trial compared SI of 15 seconds at a peak pressure of 20 cmH2O, followed if needed by a second SI of 15 seconds
at a peak of 25 cmH2O to traditional PPV for infants who after initial 30 seconds of CPAP required further intervention to establish breathing. These were provided via facemask or nasopharyngeal tune attached to a t-piece resuscitator. In both groups after the initial intervention standard resuscitation steps were carried out. The primary outcome was death or BPD at 36 weeks PMA. A data safety monitoring board (DSMB) was formed as well and it is this group that became very important to the conclusions of the study and led to its early termination. All infants were 23 weeks 0 days’ to 26 weeks 6 days’ GA. Before the study was terminated the final totals were 215 patients in the SI arm and 211 in the traditional PPV group.
The trial was stopped after the DSMB identified an excessive number of early deaths within 48 hours in the SI group. The findings were “11 of 16 early deaths in the sustained inflation group vs 1 of 3 in the standard
resuscitation group were considered possibly related to allocation group”. A number of these deaths occurred in the highest risk group of those born at 23-24 weeks but it was enough to stop recruitment.
With respect to the primary outcome the results showed no difference between the two approaches. In saying this however, if the study did not recruit enough patients as planned to demonstrate a difference one has to question whether the study had enough power to find a benefit.
To answer this question the authors performed a Bayesian Analysis to determine the probability that adding more patients would have led to a different conclusion. That is to determine if they would have found a difference favouring SI. In the end they found that their conclusions would not have changed. Sustained inflations in infants from 23 weeks 0 days’ to 26 weeks 6 days’ GA do not confer a benefit and may be associated with a higher likelihood of death within 48 hours of birth.
What do we do with these results?
I think this is it. I can’t see a research ethics board allowing another study at this point. This by neonatal standards was a big study given the relative scarcity of infants at these gestational ages. The fact that no difference was found in rates of death or survival with BPD for those at highest risk of these outcomes suggests to me that looking at older GA at birth will not produce different results. Sustained inflation to establish FRC and initiate respiration was a good concept backed by animal research. Moreover, clinical work out of Edmonton in recent years suggested potential benefits but with the publication of this study I suspect we will need as a neonatal community to look at other strategies to decrease rates of BPD. Concerns over increased risk of death in my opinion mean this ship has SAILed,
Just about all of our preterm infants born at <29 weeks start life out the same in terms of neurological injury. There are of course some infants who may have suffered ischemic injury in utero or an IVH but most are born with their story yet to be told. I think intuitively we have known for some time that the way we resuscitate matters. Establishing an FRC by inflating the lungs of these infants after delivery is a must but as the saying goes the devil is in the details.
One hundred and sixty five infants comprised this cohort. Overall, 124 (75%) infants were in the high volume group compared to 41 (25%) with a mean VT<6 mL/kg. Median Vt were 5.3 (4.6-5.7) ml/kg for the low group and 8.7
(7.3-10.6) mL/kg which were significantly different. When looking at the rates of IVH and the severity of those affected the results are striking as shown in the table. Hydrocephalus, following IVH developed in 7/49 (14%) and 2/16 (13%) in the >6 mL/kg and <6 mL/kg VT groups. Looking at other factors that could affect the outcome of interest the authors noted the following physiologic findings. Oxygen saturations were lower in the low volume group at 6, 13 and 14 min after birth while tissue oxygenation as measured by NIRS was similarly lower at 7,8 and 25 min after birth (P<0.001). Conversely, heart rate was significantly lower in the VT>6 mL/kg group at 5, 20 and 25 min after birth (P<0.001). Fraction of inspired oxygen was similar in both groups within the first 30 min. Systolic, diastolic and mean blood pressure was similar between the groups. What these results say to me is that despite having lower oxygen saturations and cerebral oxygen saturation at various time points in the first 25 minutes of life the infants seem to be better off given that HR was lower in those given higher volumes despite similar FiO2. Rates of volume support after admission were slightly higher in the high volume group but inotrope usage appears to be not significantly different. Prophylactic indomethacin was used equally in the two cohorts.
Thoughts for the future
Once a preterm infant is admitted to the NICU we start volume targeted ventilation from the start. In the delivery room we may think that we do the same by putting such infants on a volume guarantee mode after intubation but the period prior to that is generally done with a bag and mask. Whether you use a t-piece resuscitator or an anesthesia bag or even a self inflating bag, you are using a pressure and hoping not to overdistend the alveoli. What I think this study demonstrates similar to the previous work by this group is that there is another way. If we are so concerned about volutrauma in the NICU then why should we feel any differently about the first few minutes of life. Impairment of venous return from the head is likely to account for a higher risk of IVH and while a larger study may be wished for, the results here are fairly dramatic. Turning the question around, one could ask if there is harm in using a volume targeted strategy in the delivery room? I think we would be hard pressed to say that keeping the volumes under 6 mL/kg is a bad idea. The challenge as I see it now is whether we rig up devices to accomplish this or do the large medical equipment providers develop an all in one system to accomplish this? I think the time has come to do so and will be first in line to try it out if there is a possibility to do a trial.
We have all been there. After an uneventful pregnancy a mother presents to the labour floor in active labour. The families world is turned upside down and she goes on to deliver an infant at 27 weeks. If the infant is well and receives minimal resuscitation and is on CPAP we provide reassurance and have an optimistic tone. If however their infant is born apneic and bradycardic and goes on to receive chest compressions +/- epinephrine what do we tell them? This infant obviously is much sicker after delivery and when the family asks you “will my baby be ok?” what do you tell them? It is a human tendency to want to reassure and support but if they ask you what the chances are of a good outcome it has always been hard to estimate. What many of us would default to is making an assumption that the need for CPR at a time when the brain is so fragile may lead to bleeding or ischemia would lead to worse outcomes. You would mostly be right. One study by Finer et al entitled Intact survival in extremely low birth weight infants after delivery room resuscitation.demonstrated that survival for infants under 750g was better if they had a history of CPR after delivery. The thought here is that more aggressive resusctiation might be responsible for the better outcome by I would presume establishing adequate circulation sooner even if the neonates did not appear to need it immediately.
The Canadian Neonatal Network
In Canada we are fortunate to have a wonderful network called the Canadian Neonatal Network. So many questions have been answered by examining this rich database of NICUs across the county. Using this database the following paper was just published by Dr. A. Lodha and others; Extensive cardiopulmonary resuscitation of preterm neonates at birth and mortality and developmental outcomes. The paper asked a very specific and answerable question from the database. For infants born at <29 weeks gestational age who require extensive resuscitation (chest compressions, epinephrine or both) what is the likelihood of survival and/or neurodevelopmental impairment (NDI) at 18-24 months of age vs those that did not undergo such resuscitation? For NDI, the authors used a fairly standard definition as “any cerebral palsy (GMFCS1), Bayley-III score <85 on one or more of the cognitive, motor or language composite scores, sensorineural or mixed hearing impairment or unilateral or bilateral visual impairment.” Their secondary outcomes were significant neurodevelopmental impairment (sNDI), mortality, a Bayley-III score of <85 on any one of the components (cognitive, language, motor), sensorineural or mixed hearing loss,or visual impairment.sNDI was defined as the presence of one or more of the following: cerebral palsy with GMFCS 3, Bayley-III cognitive, language or motor composite score <70, hearing impairment requiring hearing aids or cochlear implant, or bilateral visual impairment”
What did they discover?
It is a fortunate thing that the database is so large as when you are looking at something like this the number of infants requiring extensive resuscitation is expected to be small. The authors collected data from January 1, 2010 and September 30, 2011 and had a total number of infants born at less than 29 weeks of 2760. After excluding those with congenital anomalies and those who were born moribund they were left with 2587. From these 80% had follow-up data and when applying the final filter of extensive resuscitation they were left with 190 (9.2%) who received delivery room CPR (DR-CPR) vs 1545 who did not receive this.
Before delving into the actual outcomes it is important to note that neonates who did not receive DR-CPR were more likely to be born to mothers with hypertension and to have received antenatal steroids (89 vs 75%). With these caveats it is pretty clear that as opposed to the earlier study showing better outcomes after DR-CPR this was not the case here.
The results are interesting in that it is pretty clear that receiving DR-CPR is not without consequence (higher rate of seizures, severe neurological injury, BPD). Looking at the longer term outcomes though is where things get a little more interesting. Mortality and mortality or neurodevelopmental impairment are statistically significant with respect to increased risk. When you take out NDI alone however the CI crosses one and is no longer significant. Neither is CP for that matter with the only statistically significant difference being the Bayley-III Motor composite score <85. The fact that only this one finding came out as significant at least to me raises the possibility that this could have been brought about by chance. It would seem that while these infants are at risk of some serious issues their brains in the long run may be benefiting for the neurological plasticity that we know these infants have.
The study is remarkable to me in that an infant can have such a difficult start to life yet hope may remain even after dealing with some of the trials and tribulations of the NICU. Parents may need to wade through the troubling times of seizures, long term ventilation and CPAP and then onto a diagosis of BPD but their brains may be ok after all. This is one of the reasons I love what I do!
The metabolic syndrome describes the development as an adult of centripetal obesity, high blood pressure, high triglycerides, elevated blood sugar and low HDL cholesterol. These constellation of problems significantly increase the risk of cardiovascular disease, stroke and diabetes.
The theory here is that conditions in utero in which the fetus is chronically deprived of blood flow and nutrition lead to a tendency towards insulin resistance. The body is essentially trying to use any energy it is receiving to stay alive in an environment in which resources are scarce. Given that situation, resisting the effects of insulin by preventing storage of this needed energy serves a useful purpose but in the long run may be detrimental as the body become programmed to resist the effects of this hormone.
What if this programming could be overcome?
Breast milk certainly has many incredible properties and as we learn more we discover only more applications. My previous post on putting breast milk in the nasal cavity is just one such example (Can intranasal application of breastmilk cure severe IVH?). In 2019 Dr. Hair and Abram’s group looked at this with respect to insulin resistance and with potential extrapolation to the metabolic syndrome in their paper Premature small for gestational age infants fed an exclusive human milk-based diet achieve catch-up growth without metabolic consequences at 2 years of age. Texas Children’s Hospital uses an exclusive human milk diet for premature infants with the following criteria GA of <37 weeks, BW of ≤1250 g, with the diet maintained until approximately 34 weeks PMA. Exclusive human milk is provided through a combination of mother’s own milk and Prolacta instead of a bovine based human milk fortifier. In this study they were able to prospectively track 51 preterm infants of which 33 were AGA and 18 SGA. The first visit (visit 1) was performed at 12–15 months CGA and the second visit (visit 2) was at 18–22 months CGA. The question at hand was whether these children would experience catch up growth at 2 years of age and secondly what their levels of insulin might look like at these times. Higher insulin levels might correlate with levels of insulin resistance with higher levels being needed to maintain euglycemia. As a measure of insuline resistance the authors used the calculation of the Non-fasting homeostatic model of assessment-insulin resistance (HOMA-IR) = (insulin × glucose)/22.5 which has been validated elsewhere. Protein intakes were equal for both groups at about 4 g/kg of human milk protein.
The Results Please
The SGA group had greater weight gain between visit 1 and 2 as evidenced by a significant difference in the change in BMI z-score, AGA −0.21±0.84 vs.SGA 0.25±1.10. I suppose this isn’t too shocking as we know that many babies born SGA experience catch up growth after discharge. What is surprising and once again speaks to the power of breast milk is the impact observed on insulin levels and resistance to the same as measured by the HOMA-IR (AGA babies are the left column and SGA the right).
The adjusted p vlaues for glucose were 0.06 with insulin and HOMA-IR being 0.02. What does this mean? Well, these are not fasting insulin levels which would be ideal but what it does say is that at fairly comparable glucose levels the level of insulin is higher in former AGA babies and the level of insulin resistance lower in the SGA infants! This result is quite the opposite of what previous studies have shown as referenced above. Aren’t these growth restricted infants supposed to have had insulin resistance in utero and been programmed for life to have insulin resistance and as adults develop the metabolic syndrome? This study falls short of making any claims about the latter as these infants are only two years of age. What this study provides though is certainly a raised eyebrow. There will be those of course that look at the size of the study and dismiss it as being too small but at the very least this study will lead to further work in this area. This paper though adds to the mystery around the potential impacts of breast milk and certainly provides strength to the thought that perhaps breastmilk should be the exclusive source of nutrition for preterm infants in the NICU. While I understand that not all women are able to produce enough for their own infants or may choose not to for a variety of reasons, with access to donor milk supply this could become a reality. The cost savings to the health care system by preventing insulin resistance would be many fold greater than the cost of donor milk in the newborn period.
Another intriguing question will be whether use of an exclusive human milk diet with use of only mother’s own milk will have similar effects or even greater impact on glucose homestasis later in life. I think the authors are to be commended for their dedication to work in this field and I certainly look forward to the next publication from this group.