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  • Blog Entries

    • By AllThingsNeonatal in All Things Neonatal
         0
      Intubate-Surfactant- Extubate or INSURE has been around for awhile. The concept is to place an ETT while an infant is first on CPAP and then after pushing surfactant in quickly remove the ETT and put back on CPAP. This does not always go as planned though. If after surfactant the FiO2 remains above 30% many people would keep the ETT in place as they would surmise that the infant would fail if the tube was removed. They would probably be right.
      Sustained inflations have fallen out of favour ever since the SAIL trial results were published and written about here . Having said that, the concept of using sustained inflation is to open the lung and expand closed alveoli to improve both oxygenation and gas exchange. Much like giving inhale nitric oxide to a collapsed lung is unlikely to make much difference, the question could be asked whether giving surfactant to a lung that is most collapsed will fail to deliver this compliance improving medication to the areas of the lung that most sorely need it. Our Italian colleagues therefore decided to undertake a study to look at providing surfactant to lungs after a recruitment manouver and see if this made a difference to the meaningful outcome of extubation failure after surfactant provision. The results are intriguing and as such here we go in looking at the study.
      Optimizing Lung Expansion
      The trial is the Lung recruitment before surfactant administration in extremely preterm neonates with respiratory distress syndrome (IN-REC-SUR-E): a randomised, unblinded, controlled trial and involved 35 NICUs in Italy. All infants enrolled were born from 24 + 0 weeks to 27 6/7 weeks gestational age at birth and all < 24 hours of age at enrollment. Each baby had to be on CPAP at the time of randomization and meet prespecified failure criteria of FiO2 of 0·30 or greater for target SpO2 of 87% to 94% for at least 30 min or in 10 Infants for rapid deterioration of clinical status or if pCO2 was > 65 mm Hg with a pH less than 7·20. Regardless of which arm they were randomized to all infants received 1-2 sustained inflation breaths using 25 cm H2O for 10-15 secs using a t-piece resuscitator after being started on CPAP as was the practice at the time. After randomization which could not be blinded, patients were then either given surfactant via INSURE without any further strategy for opening the lung or received the IN-REC-SUR-E approach. The latter involved putting the infant on high frequency oscillation starting with settings of mean airway pressure 8 cm H2O; frequency 15 Hz; ΔP15 cm H2O; and inspiration to expiration ratio of 1:2. Using this modality infants underwent stepwise recruitment methods prior to administering surfactant (poractant). The primary outome was the need for mechanical ventilation within the first 72 h of life. Infants met the primary outcome if they were not extubated within
      30 min after surfactant administration or required reintubation before 72 h of life.
      The Results
      Based on a power calculation the authors needed 103 infants in each arm and they recruited 107 in the treatment and 111 in the control arm. In the per-protcol allocation 101 received the treatment and 111 the contol. While the strategies for extubation were not set out to be equal (units were allowed to extubate to anywhere from +6 to +8 for pressure levels), the groups were not different 7·0 cm H2O, SD 0·4 for the experimental group and control arms. Given the steps taken to open the lung in the lung recruitment arm, the FiO2 was lower at 28% prior to surfactant provision in the treatment group than in the usual INSURE approach at 42% prior to surfactant provision. All infants were extubated within 30 minutes of receiving surfactant. As the results demonstrate, whether there was an intention to treat analysis or per-protocol analysis the babies who received the intervention were more likely to remain extubated. The number needed to treat was 7 which is a pretty powerful measure. Interestingly, looking at secondary outcomes there are some interesting trends as well including less mortality which on a per-protocol analysis was significant but also a trend towards more PVL at 9% in the treatment arm and 4% in the control. The mean times to surfactant administration were 4 hours in the treatment group and 3 hours in the control but the high frequency manoeuvre had a mean duration of only 30 minutes. It is possible that the use of high frequency could have blown off CO2 to very low levels but I am uncertain if the short reduction in pCO2 could have contributed significantly to reduced cerebral perfusion if that trend is representative of something. Interestingly, pneumothroaces were not different between groups as no doubt as a reader you might wonder if use of high pressures to recruit the lungs when they are non compliant might have led to air leaks.
      So it worked, now what?

      First of all, the results to me make a lot of sense. Opening the lung before delivering surfactant and then seeing better chances of staying extubated doesn’t really surprise me. Some questions that come up now for me would be how this strategy would fare in those who are older at birth. I suspect given the greater chest wall support and lower likelihood of severe RDS this strategy might be even more effective at reducing FiO2 or perhaps CPAP need in terms of duration after extubation. I would think it unlikely to make a difference in reintubation though as most would remain extubated regardless. That is for another study though with a different outcome.
      There will be centres that don’t like the use of HFOV for recruitment so what other strategies could be used in lieu of this? I hate to say it but there will also be calls to have a much larger study specifically designed to look at the secondary outcomes. Would a larger study find a significant increase in PVL or demonstrate that it was just a random finding? Might mortality be proven to be lower and even more so?
      Regardless of the above what I think this paper does is give us reason to pause before giving INSURE and ask ourselves if we have done what we can to open the lung after intubating before rushing to squirt the surfactant in. Maybe increasing the provided PEEP and lowering the FiO2 somewhat before giving surfactant will help with distribution and increase your chances of first being able to extubate and secondly when you do keeping the tube out!
    • By AllThingsNeonatal in All Things Neonatal
         0
      I recently had the honour of being asked to present grand rounds at the University of Manitoba. My former Department Head during the question period stumped me when he asked me what role angiotensin converting enzyme 2 receptor (ACE2) has in pediatric COVID19. Like all great teachers, after I floundered and had to confess that while I was aware there is a role in COVID19 I wasn’t sure of the answer, he sent me a paper on the subject. The reality is that a very small percentage of COVID19 illness is found in children. Some estimates have it at 2%. Why might that be?
      It’s what’s in the nose that matters
      What has been known for some time know is that the point of entry for SARS-CoV-2 is the nasal epithelium. What is also known is that the receptor that the virus binds to in order to gain access to the host. Such binding and what happens after the virus gains entry to the body is shown in this figure depicting the life cycle of SARS-CoV-2.
      In a research letter by Bunyavanich et al Nasal Gene Expression of Angiotensin-Converting Enzyme 2 in Children and Adults looked at 305 patients from ages 4-60 years to examine biomarkers of asthma. In the course of looking at the nasal epithelium of these patients, they found age related differences in the expression of ACE2 receptors as shown in the following figure.

      I think the results somewhat speak for themselves. The younger you are the less receptors you have. If you have less receptors maybe you are less likely to contract the virus!
      What we don’t know
      This research leads to some interesting questions. Drugs such as losartan and valsartan already exist and function by blocking he ACE2 receptor. Could blockade help to limit the spread of infection? I am not aware of any such trials going on at the moment but something worth looking at.
      The other point that needs to be raised is that the most vulnerable group of ages >60 were not looked at in this study. The trend would certainly indicate that with age we would expect the receptor numbers to increase but since we don’t actually have the data in the older groups we don’t know if receptor numbers start to fall again with age. Similarly we don’t know below the age of 4 what receptor numbers are like. In examining risk of vertical transmission it is worth noting that the recent placental positive RT-PCRs as in Detection of SARS-COV-2 in Placental and Fetal Membrane Samples. In that study while 3 of 11 placental membranes tested positive, none of the newborns were infected. Could it be the fetus and newborn is protected by having very little density of ACE2 receptors? Something to look at and will be no doubt.
      Regardless, in the fight against COVID19 maybe one direction for therapeutic targeting should be addressing this receptor and seeing if there is something we can’t do to make it less susceptible to binding.
    • By AllThingsNeonatal in All Things Neonatal
         1
      Phenobarbital at least where I work has been first line treatment for seizure control for as long as I can recall. We dabbled with using phenytoin and fos-phenytoin in the past but the go to tried and true has been phenobarbital for some time. The use of this drug though has not been without trepidation. Animal studies have linked phenobarbital to increases rates of cerebral apoptosis. Additionally, in a retrospective comparison of outcomes between seizures controlled with phenobarbital vs Levetiracetam, the latter came out ahead in terms of better long term developmental outcomes. This study from 2013 was entitled Adverse neurodevelopmental outcomes after exposure to phenobarbital and levetiracetam for the treatment of neonatal seizures. Purists of course would argue the need for a prospective trial and that is what we have to chat about here.
      Levetiracetam vs Phenobarbital
      The study in question was a multicenter randomized phase IIb trial (searches for a dose that provides biological activity with the minimal side effect profile) that compared two doses 40 mg/kg and 60 mg/kg of Levetiracetam with standard doses of phenobarbital. The study was done by Sharpe C et al and called Levetiracetam Versus Phenobarbital for Neonatal Seizures: A Randomized Controlled Trial.
      In this study patients were randomized to receive levetiracetam or control phenobarbital treatment group in a 60:40 allocation ratio by using a block randomization strategy and stratified by site. The trial design is shown in the diagram below.

      The study was designed to not delay institution of the accepted treatement with phenobarbital as usual first line treatment of seizures by more than 1 hour. The strength of this study was that the authors used electrographic seizures confirmed by continuous EEG monitoring. The efficacy of medication effect was blindly interpretted by two independent electrophysiologists. in other words the authors went out of their way to ensure these were real seizures and moreover that any changes to medications were decided upon after interpretation of effect by people remote from the study. The primary outcome though in comparison to the aforementioned retrospective study was a short one. In this study the primary outcome was initialy absense of seizures for 48 hours but then was changed part way through the study to 24 hours. The change was a practical one since it was noted after data collection that in many cases EEG monitoring had been stopped prior to 48 hours.
       
      The Results
      Honestly it is the results that led me to want to talk about this study. They are the exact opposite of what i thought they would be. Based on my own experience with Levitiracetam seeming like a wonder drug when it comes to seizure control I expected the results to favour it. Not the case.
      To say that phenobarbital crushed the competition is an udnerstatement. Having said that the incidence of side effects were higher with phenobarbital as well. Hypotension, respiratory suppression, sedation, and requirement for pressor support, were more common. Nonetheless, this study also included patients with HIE and found even in this subgroup phenobarbital was superior. This is important information as one could speculate that earlier seizure cessation in those with anoxic injury already could be especially beneficial.
      What do we do with these results?
      As the authors point out this is a study of short term outcomes. In the trial about long term outcome it was clear that treatment with phenobarbital leads to worse outcome than with levitiracetam. Having said that it was a retrospective study so the next step will be to conduct long term outcome studies to see effects. This presents the possibility of an interesting conundrum. What if the newer drug is inferior to tried and true phenobarbital at controlling seizures but leads to better long term outcome? Would you consider allowing seizures to persist longer than you might otherwise want to in the short term but then be able to reassure families that the long term outlook is bettter? The side effect profile of levitiracetam is such that I think neurologists want to use it but the other possibility is that there is another newer anticonvulsant that will need to be tested as wouldn’t it be great not to have to choose either poor acute seizure control but better long term outcome vs better seizure control with concerning long term outcome? As a parent I have no doubt watching a child eize would be terrifying and you would want it to end as soon as possible but the question with phenobarbital is at what cost?
       
    • By AllThingsNeonatal in All Things Neonatal
         0
      It’s Father’s Day so why not put out a post about a role for father’s in resuscitation. Given that we are talking about a parent being present for resuscitation after delivery and the mother will have just delivered, what follows is a discussion about having the other parent present at the ensuing resuscitation if needed. This will of course not always be a father as in female same sex parenting so what follows could apply to any situation in which there are two parents present and one has just delivered.
      Since I was a resident this question has been batted around. During a resuscitation is it better to have families present or not? Certainly work has been done in this area which has demonstrated that from the families perspective this is a worthwhile pursuit. Families wish to be present and as a parent myself I would say it would be far more frightening to be kept out of the room than invited in to see what is going on. A mind can often conjure up scenarios that are far worse than actually exist if left to ourselves. I think in many centres now this is the case that families are invited into the room when their infant is being resuscitated but looking at things from another standpoint the question becomes what effect this has on the team doing the work? Does the team perceive that their workload is increased and if so could this affect performance?
      An Answer to this question?
      Dr. Schmölzer and his team in Edmonton (my former place of work) have atttempted to answer this question by looking at initial resuscitations in the delivery suite. Their study Does parental presence affect workload during neonatal resuscitation? used a tool I was unfamiliar with called the multidimensional National Aeronautics and Space Administration Task Load Index (TLX) survey to assess workload. After a resuscitation team members were invited to fill out the survey anonymously and in total 204 submissions were done. Degree of intervention after delivery included requiring stimulation 149 (73%) and suction 130 (64%), 120 (59%) continuous positive airway pressure, 105 (52%) positive pressure ventilation, 33 (16%) intubation, 10 (5%) chest compression, and 4 (2%) reported administration of epinephrine during resuscitation.
      Results and Thoughts
      Looking at the raw scores on the TLX the difference was highly significant in favour of having a parent present.
      When further subdividing by apgar scores an interesting finding emerges in that as the apgar score increases the workload decreases. Even in the lowest apgar range the workload though appears to be equivalent.
      I wonder if the finding results from being able to kill two birds with one stone? Part of the duty for any health care provider performing a resuscitation is to inform the parent of what is happening. When a patient is not doing well a provider might feel distracted and torn between providing the immediate care required and keeping the family abreast of what is happening. Having the family member present to see exactly what is going on reduces the amount of communication using descriptions and having to explain what they mean. Being able to point at an infant on CPAP and having respiratory distress for example is far easier with the parent present to point at the finding of indrawing than taking the time to explain it. I suppose the number of questions might even be lower in that circumstance. If a baby is quite ill at birth though and receiving chest compressions or epinephrine I would imagine it would be difficult to educate the family concurrently so explaining in detail what has been happening might be deferred to a later time point and hence the workload might be no different. What the data does suggest to me though is that in addition to previous research demonstrating benefits of families being part of the resuscitation for themselves, the team is no worse off in terms of workload and might even benefit from having them there as well.
      The next logical study will look at resuscitations on the unit rather than in the case room but I think the question that was talked about as a resident can be put to rest.
  • Upcoming Events

    • 29 October 2020 Until 30 October 2020
      0  
      Visit www.signec.org for more info!
       

       
       
    • 17 November 2020
      1  
      The 17th of November each year is the World Prematurity Day. Originally started by parent organisations in Europe in 2008, the World Prematurity Day is an international event aiming at high-lighting the ~15 million infants born preterm each year.
      Read more about this day on the March of Dimes web site, and on Facebook.
    • 01 October 2021 Until 03 October 2021
      1  
      First announcement of 
      Recent advances in neonatal medicine
      IXth International symposium honoring prof. Richard B. Johnston, MD, Denver, US
      1-3 Octobe 2021, in Würzburg, Germany
      Find more information in the attached folder.
      First_Announcement_01.2020.pdf
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