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  • Blog Entries

    • By AllThingsNeonatal in All Things Neonatal
         0
      The Canadian Pediatric Society has a statement on the use of premedication before non-emergent intubation which was written in 2011 and reaffirmed in 2018. After reviewing available medications for use the recommended strategy was atropine, fentanyl and succinylcholine. This combination does involve three different medications, the first being to prevent bradycardia, the second to sedate and the third to paralyze. With the use of three medications however there is always room for error so it is very alluring to try and use one medication to provide optimal conditions for intubation. As a matter of fact I once tried thiopental as a single agent as a fellow (unpublished) which never saw the light of day due to difficulties with recruitment. Nonetheless I was after a simpler solution to providing good conditions for intubation so it is not surprising that others are also looking at single agents as well.
      Propofol Would Seem Like a Good Contender
      Propofol has been used in the adult and Pediatric world for some time. It causes a decreased level of conciousness and amnesia surrounding the events for which it was given. It is short acting often wearing off within minutes which would seem perfect for procedural sedation. On the downside one of its side effects is hypotension so in a fragile neonate this might be something to be watch for.
      Dose finding study
      de Kort et al published Propofol for endotracheal intubation in neonates: a dose-finding trial this month. It is an interesting study design for those unfamiliar with dose finding studies. The goal was to begin with a low but starting dose for propofol at 1 mg/kg/dose and escalate by 0.5 mg/kg/dose until adequate sedation was reached WITHOUT signficant adverse side effects. Moreover the authors built on previous work in this area to attempt to break the patients into 8 groups as shown in this figure.
      All patients were less than 28 days so allocation was based on gestational age and whether a patient was greater or less than 10 days of age at dosing. Level of intubation readiness was evaluated using a standardized tool called the Intubation Readiness Score.
      Side effects were hypotension, myoclonus,
      chest wall rigidity, persistent respiratory and/or circulatory failure and bronchospasm. Blood pressure was assessed via an indwelling catheter if available or by cuff if not available. Importantly any mean blood pressure after provision of propofol less than the gestational age met the criteria for declaring hypotension.
       
      The Findings
      The study was terminated early due to low inclusion in some groups after 91 total patients had been enrolled. In the end there were only enough patients in Groups 3 (26 – 29 weeks and <10 days) and 5 (30 – 36 weeks and < 10 days) enrolled to analyze fully. The results of the dose finding analysis are shown below.
      Walking through group 3, there were 5 patients enrolled at the 1 mg/kg level and based on poor levels of sedation in all the dosing for next 5 were increased to 1.5 mg/kg. As intubating conditions improved, the authors found that at a dose of 2 mg/kg while conditions were optimal, hypotension became a significant problem with 59% being hypotensive. The management of hypotension included 54% needing volume resuscitation and inotropes in 10%. Curiously the hypotension often did not appear until 2 hours or more after drug delivery. When the authors did a step down to 1.75 mg/kg as a intubation dose they found it was inadequate for providing good conditions for intubation albeit with less hypotension.
      Not the right drug
      The goal of this study was to find the optimal dose that provided good intubation conditions without significant side effects. The strength of this study was that it included babies across a wide range of gestational ages from 26+0 to 36+6 weeks gestational age. While the authors were unable to recruit enough patients to fill each group the stoppage of the study made sense as it was clear that the goal of the study would not be met. Propofol would be a great single agent if it weren’t for the issues found in this study. This is not to say that the drug is a poor choice for Pediatrics but in the Neonatal world I just don’t think it has a place. I would welcome further testing on other single agent drugs but that of course is an analysis for another post!
    • By AllThingsNeonatal in All Things Neonatal
         3
      Let me start off by giving thanks to John Minski for this article and in fact for many others that have been reviewed on this blog. John is a registered respiratory therapist in Winnipeg with a passion for respiratory care like no other. John frequently sends articles my way to think about for our unit and this one was quite sensational to me. As readers of this blog I thought you might find it pretty interesting as well.
      Why Would A Mask Cause Apnea
      To begin with this seems counterintuitive as don’t we use masks when babies are apneic to help them breathe? While this is true and they are great for support, what if a baby is breathing already but has laboured respirations and you choose to apply a mask and provide PEEP to support their breathing efforts. Surprisingly there is evidence that this may induce apnea. The evidence comes from studies in term infants and one such study to demonstrate this finding was Effects of a face mask and pneumotachograph on breathing in sleeping infants by Dolfin T et al. While tidal volumes improved with facemask application, respiratory frequency after mask application dropped by 6 breaths a minute. This may have been offset by a rise in tidal volume as minute ventilation was unchanged. Regardless there was a slowing of the respiratory rate which was found in other studies as well.
      The cause of this slowing has been attributed to the Trigemiocardiac Reflex (TCR). The trigeminal nerve branches all pass through the area around the mouth and nose as shown in this figure.
      Applying the mask can cover these nerves and as they become compressed, This can trigger the TCR leading to apnea & reductions in HR and blood pressure (in the case of V1).
      What About In Preterm Infants?
      Preterm infants are a good group to study this phenomenon in as they as a group are more apt to need respiratory support after birth and have increased tendency towards apena and bradycardia compared to their term counterparts. That is what was done in a retrospective fashion by researchers from the Czech Republic who restarted research that largely occured in the early 1980s on the TCR so congratulations to them for digging this up and deciding to look at this in preterm infants.
      The Study
      Kypers KL et al published The effect of a face mask for respiratory support on breathing in preterm infants at birth in Resuscitation in late 2019. The study retrospecitively looked at the immediate delivery room outcomes for 429 infants (median (IQR) gestational age of 28+6 (27+1-30+4) weeks and divided them into those born who breathed but needed respiratory support with a mask and those who were apneic at birth.
      As shown in the above table of the 368 babies who showed signs of breathing but had a facemask applied to provide either PEEP or anticipate the need for PPV about half stopped breathing after facemask application. In the figure below it is worth noting that the median time for this to happen was only 5 seconds and the duration of apnea was almost half a minute with 80% of these babies needing PPV to come out of it. Of those who continued breathing there were marked differences in timing of respiratory support and whether sustained inflations were employed. You were also more likely to intubate the infant if they had stopped breathing.
      Lastly, there was an inverse correlation seen between gestational age and likelihood of apnea after facemask application of 1.424 (1.281 – 1.583 95% CI)
      What are the implications here?
      The TCR appears to happen in preterm infants when you apply a mask to support respiration more commonly than at term and the risk increases as GA decreases. This is not a good combination as it means that those that are at increasing risk of lung injury from positive pressure ventilation may be at higher risk of going apneic soley from placement of a mask over the mouth and nose. Yet this has been a staple of neonatal resuscitation for as long as I and I suspect almost anyone can remember.
      What I think this really begs for is a follow-up study on the use of nasal prongs placed in the nares to provide CPAP right after delivery. This approach is what we in our centre strive to do anyway but there are many centres I suspect that still employ the mask and bag to provide CPAP either through a PEEP valve or manually compressing the exit flow end of the anaesthesia bag. If compression of the tissues around the mouth and nose could be averted, could the TCR be avoided as well with the use of prongs in this fashion. If a patient goes apneic after a mask is placed over the mouth and nose and then goes on to require PPV with provision of large tidal volumes to a 26 week infants lungs the damage is likely done and the die cast that this infant will develop enough lung injury to potentially be labelled as having BPD down the road.
      I would like to thank the authors again for picking up on research that is over 35 years old and sparking new life into this area of Neonatology!
    • By AllThingsNeonatal in All Things Neonatal
         2
      In recent years we have moved away from measuring and reporting gastric residuals. Checking volumes and making decisions about whether to continue feeding or not just hasn’t been shown to make any difference to care. If anything it prolongs time to full feeds without any demonstrable benefits in reduction of NEC. This was shown in the last few years by Riskin et al in their paper The Impact of Routine Evaluation of Gastric Residual Volumes on the Time to Achieve Full Enteral Feeding in Preterm Infants. Nonetheless, I doubt there is a unit in the world that has not had the following situation happen. It is 2 AM and the fellow on call is notified that they need to come and see a patient. On arrival the bedside nurse shows them a syringe that contains dark green murky fluid. The fellow is told that NG tube placement was just being checked and this is what was aspirated. The infant is fine in terms of exam but the question is asked “What should I do with this fluid”. The decision is made that the fluid looks “gross” and they discard it and then decide to resume feedings with a fresh batch of milk. Both parties feel good about discarding what looked totally unappealing for anyone to ingest and the night goes on. If this sounds familiar it should as I suspect this happens frequently.
      Logical Fallacy
      A colleague of mine introduced me to this concept and I think it may apply here. Purdue University’s writing lab defines a Logical Fallacy in this way “Fallacies are common errors in reasoning that will undermine the logic of your argument. Fallacies can be either illegitimate arguments or irrelevant points, and are often identified because they lack evidence that supports their claim.”
      I think we may have one here that has pervaded Neonatology across the globe. Imbedded in the fallacy is the notion that because the dark green aspirates look gross and we often see such coloured aspirates in patients with necrotizing enterocolitis or other bowel disease, all green aspirates must be bad for you. The second fallacy is that the darker the aspirate the more seriously you should consider discarding it. This may surprise you but on their own there isn’t much of anything that has been shown to be wrong with them. Looking for evidence to demonstrate increased rates of NEC or other abdominal issues in an otherwise well patient finds pretty much nothing to support discarding.
      A challenge to discarding
      Athalye-Jape G et al published Composition of Coloured Gastric Residuals in Extremely Preterm Infants-A Nested Prospective Observational Study. The study was a nested one in that questions about gastric residuals were taken from two studies on the use of probiotics. As with other studies on the use of probiotics there were some benefits seen as shown in Table 2 but that is not the main reason for sharing this study with you.
       
      The main reason for the share of this paper is what is in Table 3.

      Although not significantly different the mean estimates for concentration of bile acids in the pale and dark green aspirates came close to being different. Other nutritional content such as fat, protein and carbohydrate were no different. As the bile became darker though the bile acids tended to increase. It is this point that is worthy of discussion.
      A Breakdown of the Aspirate
      I’m with you. When you look at that murky dark green fluid in the syringe it just seems wrong to put that back into a belly. Would you want to eat that? Absolutely not but when you break it down into what is in there, suddenly it doesn’t seem so bad. We assume that we would not want to refeed such putrid looking material and that is where the logical fallacy exists. What evidence do we have that refeeding that fluid is bad? As I said above not much at all. Looking at the fact that there is actual nutritional calories in that fluid and bile acids as well you come to realize that throwing it away may truly not be in the best interest of the baby. Calories may wind up in the garbage and along with them, bile acids.
      Bile acids are quite important in digestion as they help us digest fat and moreover as they enter the ileum they are reabsorbed in large quantities which go to further help digestion. In addition bile acid concentrations are what helps draw fluid into bile and promotes bile flow. By throwing these bile acids out we could see lower bile volumes and possible malabsorption from insufficient emulsification of fat.
      The other unmeasured factors in this fluid are the local hormones produced in the bowel such as motilin which helps with small bowel contractility. Loss of this hormone might lead to impairment of peristalsis which can lead to other problems such as bacterial overgrowth and malabsorption.
      Now all of this is speculative I will admit and to throw out one dark green aspirate is not going to lead to much harm I would think. What if this was systematic though over 24 or 48 hours that such aspirates were being found and discarded. Might be something there, What I do think the finding of such aspirates should trigger however is a thorough examination of the patient as dark green aspirates can be found in serious conditions such as NEC or bowel perforation. In the presence of a normal examination with or without laboratory investigations what I take from this study is that we should question are tendency to find and discard. Maybe the time has come to replace such fear with a practice of closing our eyes and putting that dark green aspirate right back where it came from.
    • By AllThingsNeonatal in All Things Neonatal
         0
      If you work in Neonatology you no doubt have listened to people talk in rounds or at other educational sessions about the importance of opening the lung. Many units in the past were what you might call “peepaphobic” but over time and with improvements in technology many centers are adopting an attitude that you use enough PEEP to open the lung. There are some caveats to this of course such as there being upper limits to what units are comfortable and not just relying on PEEP but adding in surfactant when necessary to improve pulmonary compliance.
      When we think about giving nitric oxide the importance of opening the lung can’t be stressed enough. I have heard it said many times when a baby has been found to be a “non responder” to inhaled nitric oxide that they may have been so because the lung wasn’t open. What we mean by this is that the distal alveoli are open. One can administer all the iNO in the world but if the majority of alveoli are collapsed the drug can’t get to the pulmonary vasculature and cause the pulmonary vasodilation that is so sorely needed in the presence of hypoxemic respiratory failure. Surfactant and inhaled nitric oxide in the presence of hypoxemic respiratory failure could be a great combo as one would help open the alveoli and then the iNO could address any pulmonary vasoconstriction which might be exacerbating the hypoxemic state.
      Study Tests This Theory
      Researchers in Chile led by Gonzalez A published Early use of combined exogenous surfactant and inhaled nitric oxide reduces treatment failure in persistent pulmonary hypertension of the newborn: a randomized controlled trial in the Journal of Perinatology. The concept of this study was to compare in a double blind RCT for 100 patients (based on a power calculation looking for a 25% reduction in treatment failure) whether provision of surfactant as up to 2 doses and iNO would be better than just iNO alone. Included infants needed an oxygenation index (OI = MAPXFiO2/pO2) of 20 or more to qualify and treatment failure was an OI of 40 or more. The patients recruited were similar in common characteristics including types of conditions that would benefit from iNO. RDS, meconium aspiration syndrome and pneumonia certainly have been shown to benefit from surfactant before while in the PPHN category that is questionable. In order to ensure that it was not just the primary disease but pulmonary hypertension that was present as well, all patients required confirmation of pulmonary hypertension prior to enrollment via ECHO with either a TR jet indicating a pulmonary pressure at least 2/3 of systemic or right to left shunting at the ductal or atrial level.
      The results of the study demonstrated a clear difference in the primary outcome.
      Patients receiving the combination of surfactant prior to starting iNO showed a faster reduction in OI than those receiving iNO alone. In fact the reduction in primary outcome of treatment failure was over 50% different while the power calculation had been based on only a 25% difference. That’s ok as this means there were more than enough patients to demonstrate a difference. As a secondary outcome the rate of ECMO or death was also different between the groups favouring use of surfactant.
      It works so now what?
      Who doesn’t like seeing a study that confirms what you have long believed. I feel that this study validates the teaching I received throughout the years about ensuring the lung is open before giving iNO. There are some caveats to this however. About 90% of the patients studied had conditions present (RDS, MAS, pneumonia) for which surfactant would have been indicated anyway. If this study had been done let’s say in patients with asphyxia induced pulmonary hypertension and clear lungs the surfactant may have made no difference as the lungs were already open. I mention this as I don’t think readers of this analysis need to jump to the conclusion that every time there is a patient with PPHN that you MUST give surfactant. What I think this illustrates though is the importance of first asking the question if iNO is being considered “Have I opened the lungs?”. The next time you encounter such a patient consider whether you are using enough PEEP and whether surfactant is indicated. The bottom line is if the lung isn’t open then all the iNO in the world isn’t going to make much difference!
  • Upcoming Events

    • 29 October 2020 Until 30 October 2020
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      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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