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.
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 here!@
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!
At this point your head is likely spinning when it comes to managing the PDA. Should we treat it early, late or not at all? My last post was about benign neglect which may be well and good for the unit you work in but if you believe that these ducts can cause problems and want to treat them then you can choose from indomethacin, ibuprofen or paracetamol. Paracetamol (tylenol as you may know it better) is an old dog that has learned some new tricks. The former two drugs can be harder on the kidneys so with some recent data suggesting paracetamol may be equally effective to the other two, interest has grown. I had trouble at first understanding how this drug could help close a PDA since the other two I knew were effective through their anti-prostaglandin activity. It turns out that paracetamol is as well but just through a different mechanism. Paracetamol’s effect is likely through inhibition of the second active site on the prostaglandin H2 synthase, the peroxidase (POX) component.
Oral or IV
If you asked most people which route would be more effective the guess would be IV. Oral meds take time to be absorbed so wouldn’t you want a drug that goes straight to the target tissue as quickly as possible? The answer at least from what we learned with ibuprofen was no. There is in fact a cochrane review on the subject entitled Ibuprofen for the treatment of patent ductus arteriosus in preterm or low birth weight (or both) infants. The conclusion favoured oral dosing and the reason for the greater benefit it turns out has to do with that slow absorption I talked about. While the IV dose will get the drug going where it needs to go faster and give you a quicker peak, the slow absorption of the drug gives you a longer time with a drug level above the blood level required to have the desired effect on ductal closure. In other words, slow and steady wins the race. It’s not surprising then that as knowledge and use of paracetamol spreads that similar questions would arise. This in fact led to a retrospective study looking at this exact question. Gover et al published Oral versus intravenous paracetamol for patent ductus arteriosus closure in preterm infants. which sought to examine the difference in the two routes of administration for 50 infants in their unit that received the drug for closure of a hemodynamically significant PDA. They excluded any infants who had received treatment for a PDA previously or paracetamol for pain relief so that they could really restrict the exposure to just closure of the PDA. They defined hemodynamically significant as a “moderate to large PDA, coupled with evidence of shunt burden, myocardial compromise, and continued need for significant respiratory support.” The drug was given from 3-7 days and was at the discretion of the Neonatologist. Longer courses were given for PDAs that were still open at 3 days and dosing was otherwise the same.
What Did They Find?
In terms of effectiveness the following figure maps out what happened with both oral and IV routes. For the whole 50 patients, 56% achieved closure after one course. Although the numbers are of course small, if you look at the oral group 15/19 or 79% had closure after one course vs 8/20 or 40% with IV alone. That’s quite a difference although again numbers are small here so we have to be careful about jumping to too big a conclusion (although it is in the direction we might have expected from the ibuprofen data). As this was not a randomized study it is difficult to know for certain that other factors were not at play here to explain the difference in closure rates but the authors did attempt to adjust for that and still found a benefit to oral administration.
Could this be explained by a difference in paracetamol levels in the blood? This is what I wondered about earlier in this post so maybe there is something to that? The authors looked at this as well by searching for a difference in trough levels prior to the 5th dose (no different). While it is tempting to write this off as a possibility then it is worth noting this is just one level in time. This was not a prospective, randomized study where serial levels could be taken to establish a pharmacokinetic patterns for the levels. While the one level is not different based on route I can’t help but wonder if these results are indeed real could the levels be above the minimum threshold for ductal closure longer.
An RCT will be needed to look at determining an answer here for sure but this is a great start no doubt. One thing that I can’t help but wonder about in this retrospective study is the “why” each Neonatologist chose oral vs IV. My guess is that in most cases the sicker the baby the more likely they were to receive IV. Babies who were quite sick on vasopressors or had demonstrated poor gut perfusion on ultrasound may have been more likely to get the IV form. These same patients are expected to have greater degrees of systemic inflammation and that is not good for ductal closure. Is the worse effect of IV therapy related to the drug itself or is it related to the overall state of the baby making closure less likely in the presence of inflammation?
I look forward to seeing a prospective study on this but maybe when possible for the time being it wouldn’t hurt when possible to give paracetamol orally? Interesting story that we will hear more about!
I don’t think you can be a Neonatal blogger without writing about the patent ductus arteriosus from time to time. It’s been a little while so when something floats past my desk that I find interesting I share it with you. When that article is Canadian and written by someone I collaborate with on the Canadian Pediatric Society Fetus and Newborn Committee I am even more apt to do so. In the last few years the idea of letting nature take its course with respect to the PDA has been growing. The evidence is lacking that treatment for most infants in the first two weeks of life makes a difference to important pulmonary outcomes ie. BPD. There is a growing movement asking whether treatment at all really makes a difference to these infants or whether we should just be managing the medical complications of increased pulmonary bloodflow with diastolic steal from the kidneys and intestine. The alternative of course is to treat these infants most commonly with NSAIDs and hope that side effects such as renal impairment and spontaneous intestinal perforation don’t happen. Full disclosure, I was raised to find the PDA and if hemodynamically significant treat it, so that has been my general approach. I am open to suggestion though so without further adieu let’s talk about a recent Quebec study on the topic.
University of McGill in Montreal
Anchored by Dr. Altit with the lead author being De Carvalho Nunes the experience at this hospital was recently published as Natural evolution of the patent ductus arteriosus in the extremely premature newborn and respiratory outcomes. The authors looked a specific population of infants born at <29 weeks gestational age (214 infants in total) and importantly had a reasonable number of small infants >26 weeks at birth (84) to see what happened to their PDAs in the long run. Many years ago the unit adopted a non-intervention policy with respect to treatment of PDAs and since 2015 were in a new hospital. This afforded them the opportunity to look retrospectively at a modern cohort of infants all cared for in the same environment from Feb 2015 – Sept 2019 and see what happened to respiratory morbidity over time. While this was retrospective and lacks a control group the concept here was that one could look at the rate of BPD over time and see if it was static, rising or falling and in turn you could also compare to the Canadian Neonatal Network (not done in this study) to see if your approach was leading to all sorts of morbidity.
What did they find?
The authors chose to standardize the definition of BPD:
Grade I (nasal flow cannula <1 L/min with FiO2 ≤ 70%; nasal cannula with flow of 1 to 3 L/min and FiO2 between 22 and 29%; CPAP, noninvasive positive pressure ventilation [NIPPV] or nasal cannula with flow >3 L/min with FiO2 of 21%),
Grade II (nasal flow cannula <1 L/min with FiO2 > 70%; nasal cannula with flow of 1 to 3 L/min and FiO2 ≥ 30%; CPAP, NIPPV or nasal cannula with flow >3 L/min with FiO2 between 22 and 29%; invasive mechanical ventilation [IMV] with FiO2 of 21%)
Grade III (NIMV, NIPPV or nasal cannula with flow >3 L/min with FiO2 ≥ 30%, IMV with FiO2 > 21%).
When looking at the total population including after discharge 91% of all babies greater than or equal to 26 weeks experienced ductal closure without intervention. Secondly, if you look under 26 weeks the results were hardly any different with 90% closing. Before discharge from the hospital 66% of the larger infants experienced closure prior to discharge and 76% of those under 26 weeks. Interesting finding that more infants under 26 weeks by percentage had closure.
Looking at the respiratory outcomes a total of 77% had BPD under 26 weeks of varying severity compared to 40% in the larger infants. Other morbidities were not different.
Interestingly the authors also noted a decline in Grade 2 BPD over the 5 year study.
Thoughts on the results
It’s important to look at the overall results from the Canadian Neonatal Network to see how this group compares to the rest of the country. What follows is not perfect but its a start for a discussion.
This includes all babies in the CNN under 1500g. If we use <1250g as a rough cutoff for under 29 weeks you can see that by weight the rate of chronic lung disease ranges from 30 – 100%. At 77% under 26 weeks which corresponds to babies around 750g or less (some are a little more) then the rate should be somewhere between 60 – 80% if you count babies 500 – 750g. I would say the rate of 77% overall is not bad in terms of comparison. Secondly if you look at the distribution of CLD for this group it was at their centre it was 47, 24 and 7% for Grade 1 – 3 respectively. This is particularly interesting as when you look at mild, moderate and severe in the bars above it would suggest their babies on average with a “benign neglect” approach are more mild. This approach is looking up!
One thing that I note though is that the rate of postnatal steroid use in this group was 75% under 26 weeks and 22% for those from 26-28 weeks. This represents a large increase over the mean in the CNN back in 2019 of 11.9% for postnatal steroid use. The babies under 26 weeks were also ventilated invasively for a median of 29 days. That seems a little long to me but there are no comparisons with the CNN to know for sure.
I can’t help but wonder if you are trading short term pain for long term gain. It’s hard to argue with the long term results in terms of a shift towards better rates of lower grade BPD. I do wonder though if the eventual closure of the PDA is being helped along with use of more postnatal dexamethasone. There is some data suggesting increased rates of closure with use of dexamethasone so maybe what is going on here is that rather than using NSAIDs there is a shift to long durations of ventilation and increased rates of dexamethasone use. Something for the authors to look at though.
With everything there are trade offs so maybe less NSAID use means longer ventilation and more postnatal steroids but in the end the pulmonary outcome is better? I see a prospective RCT coming to eventually settle this debate!
