New evidence to support mid line head positioning after birth in preemies?

New evidence to support mid line head positioning after birth in preemies?

In an effort to reduce the incidence of IVH many patient care bundles in the last number of years have advocated for minimal handling. As part of approach to minimal handing an effort to keep the head straight and in some centres elevated has been postulated to help with enhancing venous outflow from the head. By reducing the passive gravity aided flow from the brain back into the thorax the theory would be that this would help minimize venous pressure in the draining cerebral system. Lowering pressure would in turn theoretically reduce the risk of IVH and hopefully the most severe types. The evidence to support this practice has largely been observational in the sense that those units practising this sort of intervention have published reductions in rates of severe IVH such as reported for small baby units. The fly in the ointment however is that many changes occur in the care of these infants so definitively attributing the difference in outcomes to just one intervention such as midline head positioning with elevation of the head can be challenging.

A Study to Sort It Out

Researchers in Iran sought to answer this question with an elegant study in which 39 patients served as their own controls and had NIRS monitoring through different head positions. This study entitled The effect of head positioning on brain tissue oxygenation in preterm infants: a randomized clinical trial study by Mohamammadie et al looked at these infants over the first 48 hours of life. Each infant went through NIRS monitoring and were randomly placed in six different positions as shown in the figure.

The infants studied were those who would be most vulnerable to IVH so were all <=32 weeks and < 1500g. The authors acknowledged that they would have liked to record over the first 72 hours as this has traditionally become the period of minimal handling in care bundles but claim that they did not have enough data past 48 hours to comment.

Prior to starting positional changes ten minutes of baseline recording was done in the midline position without elevation. Each position was used for a period of 2 hours during which NIRS monitoring was performed. The goal here was to see if the amount of oxygen extraction changed with different head positions and elevations. If the extraction increased in one head position it would be thought to reflect slowed return of venous blood with further extraction of oxygen from the brain.

What did the authors find?

Since I am reporting the findings it shouldn’t surprise you that they found something here. What might surprise you though is the actual difference in what they found. If one would have to guess before sharing the results it would seem that laying the head of the bed flat would not help with venous drainage as much as a 15-30 degree elevation so let’s guess that they would find that. Also, based on a belief that the jugular veins might be kinked if you turn your head to one side or the other let’s guess that midline head positioning does make a difference. Looking at the results below, let’s see if this actually happened.

As you can see the highest NIRS recordings were found in the baseline position and in general the three positions with the head of bed elevated (Position 4-6) and when flat in the midline (Position 1). It would seem then that the anticipated benefit was shown! From a statistical standpoint the third position was found to be different as was the fourth compared to the first position.

What does it all mean though?

A statistically different finding was achieved which shows the 3rd and 4th positions are not as good as baseline for sure but what about clinical significance. The lower limit of normal for NIRS readings is about 60. The means for all of these positions were in the 70s. In fact the difference between the mean of the 3rd and 4th positions and the others were only about 2%. Is this enough to make a difference? I honestly am not sure. There is a difference that reaches statistical significance so if we accept that there may have been some disruption of venous flow is this enough evidence to totally explain the reductions in IVH that have been seen with bundles for minimal handling with positioning? There were a lot of variables here that could not be controlled such as time of day that a baby was in one position or another since it was random. Was there a lot of noise in the unit at the time of one position or another? Depending on circadian rhythms what would the cortisol levels be and might mild changes in blood pressure explain the findings since they are so small?

I don’t want to totally dismiss the findings but suspect that it isn’t just the positioning that is leading to reductions in IVH. The same units that promote small baby care are also pushing breastfeeding rates up, skin to skin care and trying to harmonize other aspects of care. If we are seeing reductions in IVH which is a wonderful thing is it all related to this? Probably not but what this study does in my mind is support the theories about enhancing venous drainage through positioning and I see no reason not to continue this practice and try to keep these infants in the mid line and avoid bothering them as much as possible as they transition from the in-utero to ex-utero environment.

Should we feed insulin to preemies?

Should we feed insulin to preemies?

It isn’t often that something comes along that causes me to raise not one but two eyebrows but I suppose the idea of adding insulin to preemies feeds is just such a thing. Apparently this research isn’t that new as there has been some previous animal research and human testing of breastmilk that revealed insulin is present in milk at concentrations of 46 microunit/mL. Testing of amniotic fluid has found even higher levels at 2500 microunits/mL! All of this insulin can’t be there by accident. If you believe in evolution as I do it can’t be by chance that all that insulin doesn’t have a role to play. By extension, since babies swallow amniotic fluid and therefore bath the developing intestine in insulin containing fluid there must be a benefit right?

Let’s do a study looking at benefits of oral insulin added to formula!

Researchers in Israel thought the same thing as they postulated that since insulin is a growth factor in the intestine that adding an oral formulation to formula may confer benefits. We know that breastmilk is better tolerated by preemies and might it be that the growth promoting effects of insulin in breastmilk is a contributing factor? There had already been a proof of concept Phase 1 study to test the use of oral insulin at 400 microunit/mL so on this go around the authors sought to perform a larger Phase 2 study looking at the primary outcome of time to full feeds. The paper is entitled Efficacy and Safety of Enteral Recombinant Human Insulin for Reduction of Time-to-Full Enteral Feeding inPreterm Infants: A Randomized, Double-blind, Placebo-Controlled Trial.

Infants included in this study were from 26-33 weeks GA with a birth weight greater than or equal to 750g and postnatal age < 7 days. Since breastmilk has insulin in it already all infants were fed formula. The insulin was NTRA as a dry powder with the dose of 400 microunit/mL chosen based on the amount known to be in amniotic fluid. The study required 76 patients but was stopped after 33 patients when a planned interim analysis found a benefit already to the intervention without any safety concerns identified.

The Results

The primary outcome was the time it took to reach full feedings defined as 150 mL/kg/d of enteral formula intake.

As you can see there was about a 1.6 day advantage favouring the group receiving insulin. This represents a 20% reduction in time to full feedings

In terms of secondary outcomes the results were also impressive even more so when one considers the small sample size. While we don’t routinely measure gastric residuals in our centre the authors did these measurements as a proxy for feeding tolerance. They defined low residuals as a goal of < 2 mL/kg in 24 hours. In the insulin group this goal was reached in 1.67 days vs 5.09 days in the placebo group. While this result had a p Value of 0.056 so therefore just missed being significant it is an interesting trend for sure. Again owing to small size while a difference in time to wean off TPN was 2.4 days shorter in the insulin group it was not significantly different. No difference it time to discharge was found but again the difference favoured the insulin group with a mean reduction of about 9 days for singletons.

Below are the growth curves for the first 28 days reflecting a mean weight increase of 768.9g in the insulin group and 643.6g in the placebo arm.

So What’s Next?

I would like to start of by saying I hope one day you say you saw it here first! I think this research is very promising and no doubt a phase 3 trial with larger numbers is on the way. This isn’t quite ready for prime time as the saying goes based on small numbers but it is reassuring. Keep in mind this isn’t for everyone. We want as much as possible to provide breastmilk to our infants as it is more than just growth that we think about and time to full feeds. The question though for the future is whether for mothers who can’t produce enough or don’t want to breastfeed whether a little insulin sprinkled into their infant’s feeding will be just what the doctor ordered. My bet is that in the future you will see this indeed come into practice but we will need to certainly wait for bigger trials to confirm the trends that we are seeing [email protected]

Poractant alpha and Bovine lipid extract surfactant go head to head!

Poractant alpha and Bovine lipid extract surfactant go head to head!

This is the one as the saying goes that you have all been waiting for! Poractant entered the scene in Canada a few years ago with a lot of promise as a great alternative to the bovine source generally used here. The volume of administration was about half and as the use of MIST/LISA rose in popularity the option to use the lower volume was of interest to many. A study out of London Ontario demonstrated however that the bovine form could be used for LISA/MIST successfully and was written about in Less Invasive Surfactant Administration with High Volume Surfactant.

What about if we look at a real head to head comparison looking at meaningful outcomes like length duration of respiratory support? To do so would require a fairly large sample and would generally be difficult to accomplish but us Canadians opted for a study design to allow this to move forward with a sample size that for a neonatal study I think at least were admirable!

The Study

The study design here was a prospective comparative effectiveness cohort study of babies all born under 32 weeks at 13 NICUs across Canada. The study in question was entitled Poractant alfa versus bovine lipid extract surfactant: prospective comparative effectiveness study and is authored by many I consider colleagues and friends! To do this study each centre agreed to start off for 6 months with the bovine surfactant for any baby that had respiratory distress syndrome and in the opinion of the team needed surfactant. After that period each centre switched to poractant for an additional 6 months. This was a pragmatic trial designed to be less rigid with respect to criteria for intubation and allow for a “real world” determination of effect of using one surfactant vs another. While the study was not randomized the collection of outcome data relied on trained abstractors for the Canadian Neonatal Network in each centre. The authors determined that to see a difference in the primary outcome would require 484 patients per surfactant group. What they obtained in terms of recruitment is shown below.

The Results Please

I realize you have been waiting with excitement about what they could have found. Sadly they didn’t find too much!

There was no difference in length of ventilation or for that matter some important outcomes like number of doses of surfactant needed (if one group needed more might they be less effective), BPD, mortality and length of stay. The authors did note a difference in rates of MIST/LISA favouring the poractant group but when they controlled for that variable still found no difference in outcomes. Important to note that though since use of MIST/LISA may reduce the outcome of interest itself but alas no difference.

As with many studies people start digging and looking at secondary outcomes to see if there is anything of interest that pops up. It is worth noting here that whatever is found based on this study design would be an association so one must be careful not to jump to causation which may or may not be at play. For fun though let’s look at a couple of things that cropped up.

When you look at the subgroup of babies 28 +0 to 31+6 weeks an increased rate of pneumothorax creeps into the picture if you received poractant. On the other hand a reduction in days of non-invasive ventilation in favour of poractant comes into play for the same cohort. There of course is the possibility given these are secondary outcomes that these came about by chance. I did find it interesting about the pneumothorax issue though as early in the study when our centre was using poractant questions came up from our staff about a perceived increase in pneumothoraces with use of poractant. In other words the findings are in keeping with what our own units experience was so I can’t help but wonder if there is something there!

What the study does in my mind is demonstrate that if you wish to use either surfactant you may. I suppose then it comes down to comfort and in part whether you believe that use of a lower volume surfactant is better for administration with MIST/LISA. If that is the case then your choice would be poractant. If you don’t care however then it may come down to cost. There has been a difference in cost but I do wonder if the gap may close with demonstration of similar efficacy in this study. If people are indifferent to utility of the two then cost will certainly be a variable to consider!

With COVID-19 the nose really does have it. Why vertical transmission & neonatal infection may be so rare after all.

With COVID-19 the nose really does have it. Why vertical transmission & neonatal infection may be so rare after all.

As awful as COVID19 has been over the last year and a half one thing has continued to perplex myself and others. Why do babies whethe term or preterm so rarely acquire the virus? Numerous studies have been able to document placental changes and infection of these tissues. On rare occasions reports have come out with evidence of neonatal infection but fortunately most are mild.

These findings have in large part contributed to the Canadian Pediatric Society practice points on three topics.

Breastfeeding and COVID-19

NICU care for infants born to mothers with suspected or confirmed COVID-19

Delivery room considerations for infants born to mothers with suspected or confirmed COVID-19

Why might babies be so resistant?

The first post on this topic was entitled What’s in your nose makes you more or less susceptible to COVID19

In this post an argument was made that the reason these infants are resistant is due to low levels of ACE-2 receptors in the nasal mucosa of children. In this study children as young as 4 years of age were found to have very low levels of this receptor (portal of entry for SARS-CoV-2) into the host. I speculated at the time that if one carried forward the findings to younger children and infants you might find there were hardly any receptors at all.

Well, someone finally did the study and confirmed what I suspected. The study report is entitled Nasal expression of SARS-CoV-2 entry receptors in newborns by Heinonen S et al. It’s not a big study but the results are consistent across  28 newborns (17 term and 11 preterm) and 10 adults. In each newborn whether term or preterm a nasal mucosal scraping was performed at 24 hours of age and used to measure by reverse-transcription quantitative PCR mRNA expression of ACE2, transmembrane serine protease 2 (TMPRSS2), neuropilin 1 (NRP1) and neuropilin 2 (NRP2) and insulin-like growth factor 1 receptor (IGF1R).

What the results show you is that babies are not just small adults. They are different yet preterm do not seem to be that different than term infants in terms of receptors. While ACE2 has garnered most of the attention when it comes to receptors for SARS-CoV-2 the others also play a role and are in general expressed to a lesser degree in neonates than adults.

Conclusions

In the previous post I argued what was in your nose makes a difference to your risk of contracting SARS-CoV-2. Really the point is what is not in your nose. Thankfully neonates do not have good expression of these receptors and that may be the biggest reason for the general protection they have from this pandemic. It has certainly a good time to be in the “have not” group!

At 22-24 weeks does practice make perfect?

At 22-24 weeks does practice make perfect?

In the book Outliers by Malcolm Gladwell he talked about 10000 hours being the threshold at which if you practiced or gained that much experience with something you could become an expert. In Sweden the approach to 22 week pregnancies and above is to resuscitate all as a strategy. I wrote about this before in At 22 weeks of gestation does your faith matter most to outcome? The information gleaned from that paper was that if you have a policy of resuscitation at these gestational ages and you compare outcomes to a centre that is selective in who they resuscitate the outcomes are better when you believe all should be resuscitated.

New Study Expands Data

The same group has published this time around the results of the same cohort from 2006-2015 but this time with developmental outcome data. The paper is entitled Outcomes of a uniformly active approach to infants born at 22-24 weeks of gestation In this paper they discuss outcomes at 234 and 24 weeks respectively in addition to the findings for 22 weeks which they covered in the paper mentioned above. The reason for sharing this study is that if I asked you to imagine going into a room right now and talking to a family at 22 – 24 weeks and predicting the outcome of their infant, my hunch is that you would not provide as rosy a picture as the group in Uppsala, Sweden.

The authors looked at a group of infants with the following breakdown by gestational age.

As you can see, there were 222 infants in total and reasonable samples at each gestational age. What differs from other larger reports such as the work by Rysavy et al in Between-Hospital Variation in Treatment and Outcomes in Extremely Preterm Infants is that in this study ALL infants were resuscitated with intention.

Not surprisingly as gestational age declines the incidence of complications rise but looking at Table 3 even at 22 weeks there was no difference in rate of NEC or need for PDA surgery. Nor was there a difference in rates of severe IVH/PVL. Rates of BPD were higher and likely attributable to the longer durations of positive pressure ventilation. Are these rates for these complications terrible though when the other option is non-intervention which for certain means death?

What about outcome?

Looking at the outcome at 2.5 years, the rate of cerebral palsy is about 1:10 to 1:20 for all GA. Hearing impairment is almost non-existent and while developmental delay is detected in 50 percent of survivors at 22 weeks only about a quarter of the infants have severe impairment.

Deciding what to do

There is no question that many of you seeing what this post was about would simply say “NO WAY” but in the end isn’t it really about a shared decision with the family? It wasn’t that long ago that we had to have a real paradigm shift in thinking about resuscitating 23 week infants. The amount of mental energy spent for teams worldwide coming to this decision was tremendous and now if you were to suggest compassionate care at 24 weeks you get a look back like you are crazy! It wasn’t that long ago that 24 weeks was considered viability in many places and now that 23 is the new 24 this is the struggle some people have now. Should we go to 22 weeks everywhere as the Swedes have? Clearly this is a decision that institutions need to look at critically and determine if they have the space to accomodate. Each infant should they survive will occupy a bed for at least 6 months. This needs to be looked at before one can just say sure this is a good idea.

In the end what the study demonstrates I believe is that the outcome at 22 and 23 weeks for that matter need not be universally dismal. There certainly is a good chance that a surviving infant will have one or more deficits but in the end I would advocate this is a conversation all units need to be having and critically look at whether each institution has the capactity to consider.

My bet is that five years from now this discussion will be moot as we will be mostly in that direction but at this time I think we are still in evolution.