AllThingsNeonatal

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!

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.

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?

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.

It isn’t often I have had the pleasure of reviewing a paper from my own center (maybe because I have been reticient to critique my colleagues) but this paper I couldn’t resist. If my colleagues are reading this then I will provide a spoiler alert that I am not planning on trashing the paper. A few years ago my colleague Dr. Yasser El Sayed (who many of you will know from his work on targeted echocardiography and ultrasound and most recently on www.pocusneo.ca) began touting the benefits of vasopressin as an inotrope. I have to confess, my knowledge of the drug was mostly at that point as a molecule that helps regulate water balance at the level of the kidney. As the saying goes you can’t teach an old dog new tricks so I suppose it has taken me some time to get around to embracing the other benefits of vasopressin. As an inotrope it has some interesting properties. It is through action on two different receptors that the appeal of this medication is derived. Firstly it acts on V1 receptors of blood vessels, causing vasoconstriction on the systemic side and supporting blood pressure and almost paradoxically in the lung at the same receptors, causes pulmonary vasodilation mediated by the endothelial release of nitric oxide. In the kidneys, as mentioned above it helps in water reabsorption through its action on V2 receptors. In other words it supports both the systemic and pulmonary vascular systems and maintains intravascular volume by preventing hypovolemia. That is a drug with some interesting properties. Case Series From Winnipeg One of our previous fellows Thomas Budniok authored Effect of Vasopressin on Systemic and Pulmonary Hemodynamics in Neonates along with Dr. El Sayed and Dr. Deepak Louis. This was a retrospecitve case series from 2011-2016 looking at patients who received vasopressin and I am delighted to say I cared for many of these babies so saw firsthand how the drug worked. The drug was typically used as a second or third line agent for hypotension and would be also be used when pulmonary hypertension complicated systemic shock as well (in addition to use of iNO). To look at the effect of vasopressin on hemodynamics, the authors used a previously validated score called the vasoactive inotropic score (VIS) = dopamine dose (μg/kg/min) + dobutamine dose (μg/kg/min) + 100 X epinephrine dose (μg/kg/min) + 10 X milrinone dose (μg/kg/min) + 10,000 X VP dose (U/kg/min) + 100 X norepinephrine dose (μg/kg/min). By looking at changes over time this gives an impression of the effect of the drug on other inotropic requirements. The authors looked at 33 episodes in 26 patients with a median starting dose was 0.3 mU/kg/min (IQR: 0.2–0.5). The Results While the starting dose was 0.3 mU/kg/min , the maximum dose was 0.65mU/kg/min (IQR: 0.4–1.2) with a duration of therapy of 37 hours (IQR: 21–69). As you can see from the first figure of the paper, mean, systolic and diastolic blood pressures all rose over time. Might this be though that the infants were just getting better or we were using other inotropes to get the effect? Also as the measurements were taken at baseline and then 6,12 and 24 hours the influence of other measures might be expected to be less but it is the VIS that may yield more information. Maybe not surprisingly, given the changes in blood pressure the following benefits to lactate and pH were also noted. The VIS scores declined from 15 (9–20) to 13 (7–20) and 10 (8–16) at 24 and 48 hours post starting of vasopressin. Although not signficant, the median number of inotropes in use went from 2 to 1 after 24 hours. As good as the medication seems to be the authors noted hyponatremia in in 21 episodes (64%) with severe hyponatremia in 7 episodes (33%). Personally I can comment that I stopped vasopressin myself in a couple patients due to this complication. Final Thoughts I suppose it goes without saying that future studies will need to look at vasopressin using a control group. Having said that I do believe this study provides some decent evidence of effect. The short time frame of analysis and the significant changes in hemodynamics and markers of perfusion with a reduction in dosing of additional inotropes suggests a decent effect of this drug. If you choose to use this medication however what prevents this from being the “perfect inotrope” is the limitation of possible hyponatremia with its use. Hyponatremia though may be seen with higher doses so I suppose the saying may apply that with vasopressin a little may go a long way!

We would do so but to be truthful we have had a very low burden of COVID illness in my province and so haven't had to deal with this issue of cleaning yet. If we had a ventilated infant with covid we would use an uncuffed tube but still put a viral filter on the inspiratory and expiratory limb of the ventilator. We would also put them in a negative pressure isolation room

After several reports providing reassurance to breastfeeding mothers, two very recent reports are giving me reason to pause. The Canadian Pediatric Society has been recommending breastfeeding if a mother has COVID19 with precautions in place; Breastfeeding when mothers have suspected or proven COVID-19. It would be heresy to suggest that a mother not be permitted to breastfeed her infant but what follows are two reports that at the very least may need to enter the discussion when a COVID19 positive mother gives birth and is deciding about route of feeding. Toronto Case Report The first report was notable not so much for breastmilk but rather that a mother with a chronic immunodeficiency and pneumonia from COVID19 had placental surfaces that tested positive on PCR for COVID19. This was the main focus of the paper Probable congenital SARS-CoV-2 infection in a neonate born to a woman with active SARS-CoV-2 infection. In the same paper though, testing of breastmilk in this mother demonstrated a positive PCR with a semi-quantitative cycle time result (there are 40 cycles of amplification of RNA in PCR testing- the further away from 40 cycles the more likely it is a true positive). The results above were positive at 2 days and negative at 7 days. One could possibly excuse this case as an anomaly since the mother in this case not only was sick but also has chronic neutropenia but then along comes another report. Second Research Report This week a second report emerged that adds to the uncertainty around breastmilk. Detection of SARS-CoV-2 in human breastmilk looks at two mothers one of whom was negative on testing of breastmilk but the other unfortunately tested positive. The authors included the following timeline which is very informative. From the timeline above you will note that in the second case the mother becomes positive at 11 days of age and the infant tests positive around the same time the milk comes back positive. The infant in this case also develops RSV which likely explains the symptoms they developed later in the course. What is concerning to me though is that in this case while the mother was COVID19 positive, she was not acutely ill. When thinking of vertical transmission this has been something that has been postulated in suspecting that those with more severe illness have higher viral loads and therefore may be capable of vertical transmission. Not the case here if the results are to be believed. Adding to the strength of the result are Ct values for SARS­CoV­2 N peaked at 29∙8 and 30∙4 in whole milk and skimmed milk respectively so this seems real. How does this differ than past testing? What intrigues me about this study in particular is that past research on transmission into breastmilk has failed to detect the virus. It could be that previous testing close to delivery was negative and that with time might the virus enter breastmilk? At eleven days I think this may be the latest testing done. In virtually all cases reported about COVID19 positives in newborns the authors have always explained the painstaking steps they took to prevent postnatal infection. I do wonder now if some of these cases may be related to a small percentage of women carrying the virus in their breastmilk. This leaves us in a tough spot. What do we tell women who are thinking of breastfeeding and have COVID19? There will need to be discussion on this but one option is to proceed with feeding accepting there may be a small risk of transmission. A second option would be to test milk but if the transmission occurs late you may miss it in hospital on initial sampling Finally it may be worth pumping and discarding milk until mothers test negative and using donor breastmilk in the meantime (or formula for those who don’t have DBM). Regardless I think this information coming out will need to be digested and centres think about how they will approach this issue. My guess is these will not be the last reports on this.

After developing a community of over 23000 people unfortunately I had to close my Facebook site due to concerns over a hack. Not to worry as I have created a new independent site to share information daily in Neonatology. I look forward to building an audience at this site and working to continue the dialogue I have come to enjoy with all the followers. I look forward to seeing you there! The New Site is at: https://www.facebook.com/allthingsneonatal2

I doubt there is a unit in the world where at least once a day a discussion ensues about whether an infant is ready to wean or come off their CPAP. For many years we have made the decision based on a variety of markers. Some people would comment on the work of breathing, others on the FiO2 or what the oxygen saturations are at the moment as we round on the patient. Our unit has been pulling oxygen histograms off the patient monitor for years now to provide a more objective measurement to determine if an infant is ready or not. What is a histogram? It is a bar graph representation of the percentage of time in a 24 hour period that an infant has spent in several different oxygen saturation ranges. A group in Alabama recently published the following paper Oxygen saturation histograms predict nasal continuous positive airway pressure-weaning success in preterm infants. which attempts to answer the question as to whether this practice has merit. What did they do? They looked at 36 babies (24 control and 12 cases) in which controls were babies who successfully weaned off CPAP when on less than or equal to 30% oxygen in the first week of life and compared them to infants who failed and had to go back on. Success was defined as remaining off CPAP for 7 consecutive days while failure was having to go back on with in 7 days of discontinuation. All infants were <1250g at birth or less then or equal to 30 weeks gestational age at delivery. Infants were enrolled prospectively in an observational case-control study. During the study goal oxygen saturations were 90-95% and oxygen histograms were monitored q6h by respiratory therapists. Importantly, during the study there was no standard approach to weaning patients off of CPAP but as per many NICUs, discontinuation occurred when FiO2 was low and there were only 1-2 events per day requiring stimulation. The authors controlled for a number of potential factors which could influence success such as GA, BW, Sex, receipt of antenatal steroids, ventilation, caffeine dose, FiO2 prior to weaning and surfactant but found no differences between groups. What did they find though? As you might expect there was a difference found and it was in the histograms. The infants who ultimately succeeded in coming off CPAP were better oxygenated in the 24 hours prior to coming off CPAP. Of note, the cases had a median FiO2 of 22% and the controls 21% which was not statistically different. Looking at the above figure you can see that there were statistically significant differences in the two groups with the babies who successfully weaned off CPAP having significantly higher levels of oxygen saturation in the 95% and above ranges. The authors concluded “The optimal value of oxygen saturation achievement >95% to predict CPAP-weaning success by Youden index was 31.6% with a sensitivity of 75% and specificity of 75%.” In other words if you have about 30% of the time spent above 95% in the 24 hours prior to coming off CPAP you have a pretty good chance of success! Applying the information Who doesn’t like a study that validates your own practice?! The study is really a beginning though as the study tells us that for babies that are mildly ill (as evidenced by being on room air or 22%) that you can utilize the histogram data to make decisions about when it is best to stop CPAP. What this study though examined is a particular population of small infants who were all taken off CPAP in the first week of life. Would the same principals apply to an older infant or one who is larger at birth? I would like to think so but there are many infants who are on oxygen with BPD who are also weaning off CPAP after many weeks of age. We use histograms in this population as well to guide our weaning but an important measurement that must be taken into account is the FiO2. I can really manipulate a histogram to show anything I want for a baby on oxygen. If it is better from one day to the next is it because the lungs have improved or has the average FiO2 simply been higher in the preceding 24 hours? Conversely if it is worse does the infant have atelectasis or pneumonia or has nursing been more restrictive in FiO2? Further studies in this area need to create an objective tool that takes into account level of support and mean FiO2 when interpreting the histogram. Failure to do so would lead at times to incorrect decisions if you solely look at a bar graph. As with everything in NICU, the devil is in the details!

Good morning or evening everyone! As we move thorough these turbulent times everyone has questions about how this story will end. My experience with social media has been one that has been evolving for some time. Recently with so many questions about COVID19 I opted for setting up Facebook Live video sessions and although they aren't a visual question and answer session they do allow for people who are watching to make comments. One of my favourite sessions so far has been with Stefan from 99nicu as shown here! https://www.youtube.com/watch?v=AwNGxiYvgLg&list=PLHmYb5bfg4U3RuEO7Jf9mC4rF_0CAHiIZ&index=10&t=33s As the number of discussions builds you will be able to find them posted all in this one playlist that I hope you will find helpful. It is so important to remember that while all we seem to hear about these days is COVID19 the reality is that we are still in the infancy of our understanding of this disease. When you think of the 250 or so reported cases of neonatal outcomes remember that many conditions have thousands upon thousands or millions of cases to help our understanding of the disease. In the case of COVID19 we are in a period where I fear there will be much back and forth or whipsawing as small but important reports have the chance of moving the needle substantially. If you find all of this confusing don't worry you are not alone. It is my hope though to help you with your jouney along the way. As mentioned here is the link to the playlists for all COVID19 related videos including several simulations for resuscitation which perhaps your centre will find useful for planning in the event you do find yourself faced with such a delivery. https://www.youtube.com/playlist?list=PLHmYb5bfg4U3RuEO7Jf9mC4rF_0CAHiIZ

You might think this title is a joke but it is actually quite serious. Volatile organic carbons (VOCs) are what give stool it’s characteristic and often very malodorous scent. These same VOCs though could serve as biomarkers for preemies at risk of NEC. In fact previous research using an artificial nose has suggested as much. In 2015 de Meij TGJ et al published a study looking at VOCs entitled Early detection of necrotizing enterocolitis by fecal volatile organic compounds analysis. They used an electronic nose to try and detect changes in VOCs before the onset of NEC. This study which included a small sample of 13 with NEC compared to 14 without found a different profile of VOCs starting about 2-3 days before diagnosis of NEC. The study was quite small though and may not have made the waves that a larger trial might have. Along comes the bigger trial This month the DOVE study was published by Probert C et al “Faecal volatile organic compounds in preterm babies at risk of necrotising enterocolitis: the DOVE study”. The study picks up where this last one left off by looking at a much larger sample of babies. They managed to recruit 1326 babies under the age of 34 weeks of whom 49 developed NEC vs 70 matched controls. Of the 49 with NEC only 32 had sufficient stool samples for analysis since not every infant stooled every day. For the study all babies in these units had each stool sample collected from birth and then frozen until ready for analysis. The samples were then analyzed from 6 days prior to the diagnosis of NEC in the cases vs a day equivalent of 6 days prior in the controls. NEC was defined as stage IIa or greater. The Results When looking at overall numbers of VOCs between cases and controls there was no difference (35.8 in cases and controls 36.4). When grouping VOCs into 9 different natural groupings (factors) though, some interesting findings emerged. The five best VOCs for prediction had the following receiver operator curves. Not dramatic curves but acceptable for a relationship overall with NEC. Each of these factors were found to be associated with different demographics. For example, factor 1 VOCs were correlated to gestational age. Factor 4 contained six correlated VOCs which are associated with formula milk feeds and age. The risk of NEC increases with the value of factor 4, raising the question of whether an elevated level of this factor could predict NEC. Another curious finding was the presence of VOCs in factors 8 that are protective against NEC. One of the VOCs is known to be produced by bifidobacteria and lactobacillus both of which are also associated with less NEC. It makes some sense then that factor 8 would be negatively correlated with NEC. What’s next? The results raise some questions for the future like how would units actually use this information? The lead time before NEC that these VOCs were identified were anywhere from about 3-4 days. Could a unit ready device be ready in the near future with point of care technology? It wouldn’t help to find out from an outside lab several days after NEC what the VOC profile was but if it was at your finger tips that might be helpful. The next issue as I see it is what if anything you can do about it. Is there a guarantee that if three to four days prior to NEC you find these VOCs rising as in factor 4 that you can prevent NEC? It is possible that the cascade towards NEC has already started and it is now unavoidable. In spite of these questions I find it quite interesting that we would be able to utilize these VOCs in such a way. One never knows if in the future an electronic nose will show up in an NICU near you!

I had the pleasure of being asked to speak to a Canadian audience of people working with newborns yesterday about the new CPS practice points for managing deliveries and newborns with suspected or proven COVID-19. Something fascinating happened over the course of the discussion and that was that we are a country divided. It didn’t help that the week prior to the CPS releasing their practice points the American Academy of Pediatrics released the following position: “Precautions for birth attendants: Staff attending a birth when the mother has COVID-19 should use gown and gloves, with either an N95 respiratory mask and eye protection goggles or with an air-purifying respirator that provides eye protection. The protection is needed due to the likelihood of maternal virus aerosols and the potential need to perform newborn resuscitation that can generate aerosols.” I don’t know how the Americans are going to deliver on bringing N95 masks to all deliveries and even acknowledge in their statement that this recommendation essentially holds as long as there are supplies. There are a lot of deliveries in the US and if every one requires all team members to have an N95 respirator (two nurses, RRT, MD) that will burn through supplies quickly! The driver of this division in the country and the AAP I believe is fear butI am not in any way judging anyone for having it in these trying times. I think it is worth looking at what is being proposed for care of the newborn by the CPS and what may be motivating this fear. Who knows it may help someone work through their own feelings on this. What has been recommended? What the CPS recommendations boil down to is this. For attendance at a delivery in which the mother is not intubated or expected to be, providers of care for the newborn should use droplet precautions. Specifically, whether the infant is going to receive PPV, CPAP or be intubated the evidence strongly suggests the newborn is delivered uninfected so an N95 is not needed to protect health care providers. Even if the baby is born vaginally and is exposed to blood and stool, the viral load in the distal tracheobronchial tree will be low to non-existent so aerosolization would not be a concern. If the mother is going to be intubated then an N95 mask should be worn instead of a surgical mask. Outside of the delivery room in the NICU one should use an N95 mask for providing care to any newborns on CPAP or other non-invasive support as well as those who are intubated. It is the last statement that I know has caused some confusion. Why is it that Dr. Narvey is suggesting that in the first 30 minutes of resuscitation we don’t need an N95 but then after the baby is moved to NICU we do? The issue is a pragmatic one. The earliest known case of a positive nasopharyngeal swab is 36 hours. This doesn’t mean of course that the earliest one can get horizontal transmission is 36 hours as this is when the health care providers decided to test. Presumably they were not lucky and timed it right so we have to expect at some point maybe hours or more earlier the baby became infected. As we get busier with more and more COVID suspect mothers there is a risk of people not “watching the clock” and therefore if we had said once 12 hours or 24 hours have elapsed use N95 masks for those on respiratory support we run the risk of someone losing track of time. There are a lot of babies who need PPV at birth though but not all eventually need CPAP so eliminating the need to use N95 masks when the evidence doesn’t support their use is a responsible way of preserving masks that are in short supply for those who truly need them based on true proven risk such as with adults with COVID pneumonia being intubated. Why is there so much fear? I blame the media to a great extent. They latch on to stories such as this one that made its way around twitter and facebook and yet there are no publications of this infant. Likely a positive infant no doubt but I suspect it was not detected minutes after birth. Then there is the case series in Jama Pediatrics that turned the world upside down a few weeks ago. I don’t know about you but my inbox was peppered with this paper from all over Canada and beyond. Looking at the paper in detail including the images is informative as what was initially touted as evidence of vertical transmission on closer inspection I think is far from it. Three out of thirty three infants tested positive on an NPA at 48 hours of age with a claim that all three had pneumonia. The authors included two x-rays for the two 40 week infants and a CT scan of the chest for the 31 week infant. Take a look at these films. I am not a radiologist but I suspect we would have reported these films as normal. The CT scan of the chest is in a 31 week infant who had RDS and enterobacter sepsis. How would one differentiate RDS, enterobacter pneumonia or COVID19? It may be possible these three babies indeed were inoculated in the first day or two with COVID19 but I am not so sure they really had disease. If you agree with my argument here then we have multiple case series demonstrating no vertical transmission and this one case series indicating possible horizontal transmission. Why then are we hearing about care providers bring N95 masks to deliveries just in case CPAP is needed? Fear is a great motivator It likely comes down to the “what if” argument. What if everyone is wrong and babies can be born with COVID19? If we had an unlimited supply of N95 masks then my answer to everyone would be “if it makes you feel better then go for it and use away”. My argument for not using them at birth is twofold. Firstly, the evidence so far is that this is not a risk and secondly we don’t have an unlimited supply of N95 masks. This creates an issue for society as a whole that if we are guided by our fear we may deprive those who truly need this resource for evidence supported high risk procedures. I believe we all have a duty to provide the best care possible and working within a system with a finite amount of resources we need to really consider what happens if we let fear override what we know from evidence. Having said all that (and this is not a cop out but reality), we are all fatigued and probably not at our best at the moment. We are fearful for our own heath and not just physicial but mental as well. I read this morning that suicide rates in the US are up 35% this year and extrapolating I would imagine that rates of depression and anxiety have gone up with it. These infants we care for deserve us to be at our very best. If fear of contracting COVID19 has reached a level for an individual that it may interfere with their ability to provide the proper steps of NRP if not wearing their “armor” in the form of an N95 mask this needs to be considered. I am not a psychiatrist nor am I pretending to be one but our mental state has a great impact on performance. I am not endorsing the use of N95 masks for everyone but I am suggesting that during this time we all take a moment and do a check in with yourself. Are you focused, are you able to think with a clear head when needed? We need to be at our best and for me I am confident that I can care for a newborn with a regular mask but I ask you since you know yourself to be truthful with yourself so we can provide the best care possible. Please everyone stay safe!

This is another hot topic out there as centers around the world struggle to determine how best to manage the mother who has contracted COVID-19 in pregnancy. There are resources out there already such as the CDC which states the following. The World Health Organization also has this to say as of yesterday. The question though is where do these recommendations come from? How strong is the evidence? Let’s begin with another Coronavirus Do you remember SARS? This was another coronavirus. Wong SF et al published Pregnancy and perinatal outcomes of women with severe acute respiratory syndrome in 2004 in which they described the outcomes of 12 women infected with the coronavirus causing SARS. In this study they sampled Evidence of perinatal transmission of virus was assessed by SARS-associated coronavirus reverse-transcriptase polymerase chain reaction (SARS-CoV RT-PCR) and viral culture on cord blood, placenta tissue, and amniotic fluid at or after delivery. None of the tested infants were found to have infection nor were any of the tissues or fluids positive. They did not test breast milk specifically but as none of the infants developed SARS one could infer that if the other samples were negative so were the breastmilk samples. The conclusion after the SARS epidemic is that vertical transmission does not occur. Moving on to COVID-19 It may surprise you but there is very little out there on breastmilk and COVID-19. Having said that, there is very little data on pregnancy and COVID-19 so the question then is how strong is the evidence for lack of transmission in breastmilk? There is really one study by Chen H et al Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records. The authors looked at 9 women presenting in the third trimester and examined outcomes from pregnancy. All of the infants were delivered via c-section and in 6 of the 9 samples of breastmilk were obtained and sampled for COVID-19. The good news was that none of the samples tested positive for the virus. I suppose the result shouldn’t be that surprising as the virus causing SARS is similar and also has not been demonstrated to lead to neonatal infection. The question then is whether one should freely breastfeed their newborn if they are known to be positive for COVID-19. Getting back to the earlier recommendations from the CDC, they read as pretty firm. Looking at the sum total of evidence I think it is safe to say we don’t have a lot of data to go by. What we have though in this situation is to look at risk/benefit. To the best of our knowledge, the COVID-19 is not transmitted into the fetus and after birth does not get into breastmilk. Both of these things appear to be quite good but as the virus spreads and more pregnant women contract the virus we may see as we get a larger sample that it is possible but I suspect this is a virus that simply doesn’t transmit to breastmilk. What if we banned breastfeeding in suspect or confirmed patients? The potential loss of immunoglobulins against COVID-19 is a real risk for the infant as they continue to live in the same home as the mother. How do we know that such antibodies exist? As for as I know for COVID-19 this hasn’t been proven yet but in the SARS epidemic a case report demonstrated that antibodies against this virus were indeed in breastmilk; SARS and pregnancy: a case report. Given that the viruses are part of the same class I would imagine the same would hold true with the new coronavirus. They may not be born with the virus but if they are receiving passive immunity from the mother that needs to be considered given that we have nothing effective (at the moment) to treat anyone. An alternative is to use donor breast milk but if we go down that road, our supplies will be exhausted before long. Weighing everything and using the best data we have at the moment my bias would be continue breastfeeding albeit with the recommendations for droplet precautions and hand hygiene as the CDC suggests. Stay safe out there everyone.

We are living in challenging times but, as a community caring for neonates and their families, we will get through this together. Canadians and others around the world are digesting a great deal of information in order to come up with a best approach to caring for mothers and infants with either suspected or confirmed COVID-19 infections. It is an imperfect science for sure as we have scarce information to go on but you may find it helpful to look at what centres are doing in terms of their approaches to delivery and care in the NICU. Please note that these are being posted in an attempt to share our collective efforts but that referral to your local health authority protocols is recommended. Protocols and other relevant information including sim/ education and processes can be shared from sites across Canada and accessed through the COVID-19 menu at the top of the site. There will no doubt be geographic differences which may be due to unit layout (single/double rooms, open bay concept, negative pressures rooms), local IPC and health authority protocols. Hopefully, though, our community can share useful resources, algorithms, videos, etc that can serve as a framework for others to use or modify to suit their needs. Thanks to all of you for your dedication, your hard work and for your caring. Please stay safe and stay healthy – we will get through this – together. Useful Links Provincial Approaches to Newborn Care COVID19 Provincial Approaches Literature Review COVID19 Literature Additional Organizational Information Ontario “Provincial Council for Maternal and Child Health – Covid 19 Practice Support Tools Interim Considerations for Infection Prevention and Control of Coronavirus Disease 2019 (COVID-19) in Inpatient Obstetric Healthcare Settings

This week on social media this seemed to be a hot topic. What should we do to protect ourselves as we start to see more mothers infected or at least suspected of having COVID-19 presenting in labour. Should we be assuming all of these infants are infected and if so should we all don personal protective equipment (PPE) including the N95 mask? Let’s see what we know so far. The Media The big concern with this began after a report of a 36 hour old newborn in China contracting the virus. This was published in Clinical Infectious Diseases in the paper A case report of neonatal COVID-19 infection in China. As the authors point out in this paper it is difficult to determine if the baby was born with the infection or was seeded with virus at birth and then tested positive at that point. This story made the news and sparked a lot of questions about whether newborns could be infected. The latest story to hit the news though is more worrisome as it leaves little to the question of when the infant was infected. Newborn baby tests positive for coronavirus in London from the Guardian as well as other sources publicized that a newborn who was swabbed within minutes of birth tested positive. This is enough to strike fear in just about everyone but there are questions that need to be answered before panic can set in. There really are little if any details about this patient. Were they symptomatic or was a nasopharyngeal swab positive for the virus alone? While it is tempting to link the infected newborn with transmission from amniotic fluid, there are other sources of virus such as blood and stool that can be present at delivery from the mother than could have yielded the positive result. What does the evidence say about amniotic fluid Bear in mind the data is sparse but here is what we know about amniotic fluid thus far. In a recent paper in the Lancet entitled Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records. some good information was found. It is important to note that all of the infants were born via c-section so the issue of potential contamination by stool or blood was greatly reduced. All of these women had their amniotic fluid sampled and all nine tested negative for the virus. Yes I realize nine samples does not totally guarantee that virus cannot be transmitted into amniotic fluid but it is certainly reassuring as they were pure samples. Also notable was that none of the babies in the study presented with any symptoms of respiratory distress. Additionally another recent paper Infants Born to Mothers With a New Coronavirus (COVID-19) in Frontiers of Pediatrics demonstrated no neonatal infections in the three infants whose parents consented to testing for COVID-19. Presumably their amniotic fluid was free of virus as well. If you look at the total number of known cases to this point in the world summarized below we know there have been now 30 infants tested in total aside from the two cases above that have been negative. Things for the most part are looking good on the neonatal front (at least at delivery) Planning for deliveries In the twitter world this week there was much discussion about this issue. To use PPE including an N95 mask or not. I would love to tell you what you should do but that is up to your own institutions and their risk tolerance. While the media can certainly sensationalize things (and these two cases above haven’t helped stop that), the evidence would suggest at this time that these newborns are not born infected for the most part. One of the issues though is sample size for sure. How many pregnant women with COVID-19 have there been to this point? Hard to say especially since not every person can be tested. For the time being though my bet is that these babies are not born viremic but may be contaminated at birth. How long the virus takes to grab hold of the newborn and possibly cause disease is a different story altogether. Once a baby is in an NICU and develops symptoms our approach must be more cautious. We will have to see where this all goes but be careful out there.