AllThingsNeonatal

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.

One of the most common conditions afflicting ex-preterm infants is chronic lung disease. Through advances in antenatal steroids, surfactant and modern ventilation we have done what we can to try and prevent this condition from occurring yet despite our best efforts CLD remains a common problem among those born at less than 1500g as is shown in the 2018 Canadian Neonatal Network data. Primary prevention is of course the ideal strategy to reduce disease but when you try and your best and an infant still has chronic lung disease what is one to do? For now we bide our time focusing on nutrition and minimizing harm from ventilation. Something new is coming and I hope it comes soon. Stem Cells to Heal BPD My former colleague Bernard Thebaud has done much work already in this field. A recent review he was part of is a good starting point to bring you up to speed; Stem cell therapy for preventing neonatal diseases in the 21st century: Current understanding and challenges. As the field advances though and we continue to see additional animal trials such as the one I will discuss here, the interest in this field continues to grow. I was drawn to a recent paper on this topic as it is not dissimilar to another trial I wrote about in which stem cells were given via breastmilk intranasally to improve outcome after IVH; Can intranasal application of breastmilk cure severe IVH? In this new trial though instead of delivering stem cells in a cephalad direction they place the rat vertically to deliver the stem cells from wharton’s jelly to the trachea and damaged lung. Stem cells from Wharton’s Jelly Moreira A et al published the following paper in Intranasal delivery of human umbilical cord Wharton’s jelly mesenchymal stromal cells restores lung alveolarization and vascularization in experimental bronchopulmonary dysplasia This study was done in four rats divided into 4 groups. Group A were rats born and raised in room air. Group B were exposed to 60% oxygen for four days to induce BPD. Group C was given experimental BPD as in Group B and then given the vehicle for stem cell delivery without stem cells. Group D then also had BPD was actually given stem cells. The timeline for the study is shown below. The results are quite impressive. Looking at the histology of the four different groups reveals the curative property of these types of cells. In essence the lung tissue architecture at the alveolar level looks almost identical to normal rat lung on the far left if the stem cells are provided through the intranasal route. Moreover, when one looks at the impact on the blood vessels in the lung using Von Willebrand Factor staining similar healing is observed. Lastly, not only were the numbers of blood vessels recovered but the thickness of the smooth muscle was reduced to that of normal rats without BPD after such treatment. Why is this so important? Past research has delivered stem cell treatment to the alveoli through an endotracheal tube. What this demonstrates is that rats held in a vertical position can have stem cells delivered into the lung where they are sorely needed. Could one take an infant on CPAP who is developing signs of CLD and do the same? The day may be coming when we prevent such infants from being reintubated just for CLD in the future. The road is long though and the use of stem cells in humans has not begun yet. The effects seen in this rat model are dramatic but will they translate into the same thing in the human? I believe so and am waiting ever so patiently for such trials to start in humans. If you are looking for the next big leap in Neonatology I suspect this is what we are looking at. The question now is when.

First off I should let you know that we do not do transpyloric feeding for our infants with BPD. Having said that I am aware of some units that do. I suspect the approach is a bit polarizing. A recent survey I posted to twitter revealed the following findings: I think the data from this small poll reveal that while there is a bias towards NG feeds, there is no universal approach (as with many things in NICU). Conceptually, units that are using transpyloric feeds would do so based on a belief that bypassing the stomach would lead to less reflux and risk of aspiration. The question though is whether this really works or not. New N of 1 Trial I don’t think I have talked about N of 1 trials before on this site. The trials in essence allow one patient to serve as a study unto themselves by randomizing treatments over time for the single patient. By exposing the patient to alternating treatments such as nasogastric or nasoduodenal feedings one can look at an outcome and get a sense of causality if a negative or positive outcome occurs during one of the periods consistently. That is what was done in the study Individualising care in severe bronchopulmonary dysplasia: a series of N-of-1 trials comparing transpyloric and gastric feeding by Jensen E et al from the Children’s Hospital of Philadelphia. The authors in this study determined that using a primary outcome of frequency of daily intermittent hypoxaemic events (SpO2 ≤80% lasting 10–180 s) they would need 15 patients undergoing N of 1 trials between nasogastric and nasoduodenal feeding. Included infants were born at <32 weeks and were getting positive airway pressure and full enteral nutrition at 36 0/7 to 55 6/7 weeks PMA. Infants who were felt to be demonstrating signs of reflux or frank regurgitation were enrolled. The findings Thirteen of 15 enrolled patients completed the study. The two who did not complete did so as their oxygen requirements increased shortly after starting the trial and the clinical team removed them and chose their preferred route of feeding. Randomization looked like this: Of the 13 though that completed and using an intention to treat analysis of the other two the findings were somewhat surprising. Contrary to what one might have thought that transpyloric would be a lung protective strategy, the findings were opposite. Overall the combined results from these 15 patients demonstrated that nasogastric feedings were protective from having intermittent hypoxic events. How can this be explained? To be honest I don’t really know but it is always fun to speculate. I can’t help but wonder if the lack of milk in the stomach led to an inability to neutralize the stomach pH. Perhaps distension has nothing to do with reflux and those with BPD who have respiratory distress with some degree of hyperinflation simply are prone to refluxing acid contents due to a change in the relationship of the diaphragmatic cura? It could simply be that while the volume in the stomach is less, what is being refluxed is of a higher acidity and leads to more bronchospasm and hypoxemic events. What seems to be clear even with this small study is that there really is no evidence from this prospective trial that transpyloric feeding is better than nasogastric. Given the size of the study it is always worth having some degree of caution before embracing wholeheartedly these findings. No doubt someone will argue that a larger study is needed to confirm these findings. In the meantime for those who are routinely using the transpyloric route I believe what this study does at the very least is give reason to pause and consider what evidence you have to really support the practice of using that route.

Inhaled nitric oxide has been around for some time now. I recall it being called at one point in medical school “endothelial relaxation factor” and then later on identified as nitric oxide. Many years later it finds itself in common usage in NICUs all over the world. Our experience though has been for treatment of pulmonary hypertension and for that it is pretty clear that for those afflicted by that condition it can be lifesaving. Over the years other uses have been looked at including prevention of BPD (turned out not to be the case). Rescue approaches therefore have found to be useful but on the prophylactic side of things not so much. Maybe starting earlier is the key? A group based out of Oklahoma has published a pilot study that raised an eyebrow for me at least. Krishnamurthy et al released Inhaled Nitric Oxide as an Adjunct to Neonatal Resuscitation in Premature Infants: A pilot, double blind, randomized controlled trial . The study set out to recruit 40 infants who between 30-90 seconds of life if requiring PPV would either get iNO 20 ppm with 30% oxygen or 30% oxygen and placebo for ten minutes. At ten minutes weaning of iNO by 1 ppm per minute for a total of 17 minutes was done. The primary outcome of interest was FiO2 required to achieve target oxygen saturations. As with many studies that seek enrollment prior to delivery this study was a challenge as well with early termination of the study after 28 babies (14 in each group) were recruited. Did they find anything interesting? In spite of the low numbers in the study, the authors did find a divergence in the FiO2 needed to achieve the target oxygen saturations. The authors conclusions were that the cumulative exposure to FiO2 was lower in the iNO group as well as the maximum exposed FiO2 of 39% vs 48% (although this almost but not quite met statistical significance. Even then this is a pilot study so inferring too much could be a dangerous thing. The study though does get one thinking but we need to be wary of letting our brains do some mental trickery. Lower FiO2 seems like a good thing given what we know about oxygen free radicals. What about rapid lowering of pulmonary vascular resistance with exogenous iNO? Is this a good thing or could other things be lurking around the corner? Could a larger study for example find a higher rate of pulmonary hemorrhage with rapid reductions in PVR? The authors did not find harm in the study but again with small numbers it is hard to conclude too much. What this small study does though is raise many questions that I think could be interesting to answer. If a patient needs less FiO2 at 17 minutes after study entry might there be less perceived need for higher PEEP if ventilated or CPAP levels if on non-invasive support? Less pressure could lead to less risk of pneumothorax (or more perhaps if under treated but with respiratory distress. Less pressure might also influence longer term risks of BPD from barotrauma or volutrauma for that matter. Regardless this is only the beginning. I have no doubt there will be further trials on the way. The trick will be as in this study to obtain consent unless a deferred consent could be obtained but I have my doubts about getting that. Nonetheless, wait for more to come!

The Ortolani and Barlow manouvers are probably the two most requested parts of the physical exam that students ask to be shown. We line up several medical students who take turns applying the steps of abduction and then adduction, testing the stability of the hips. We routinely give oral sucrose, position in kangaroo care or breastfeed while performing other noxious stimuli such as heel lancing but at least in my centre give nothing for manipulating the hips in such a fashion. How can we determine if a newborn feels pain? In a recent paper entitled Neurophysiological and behavioral measures of pain during neonatal hip examination by Pettersson M et al they used three methods to assess pain during the newborn hip exam. These were the Premature Infant Pain Profile‐Revised (PIPP‐R) scale which is generally used for such assessment as well as two relatively novel ways in the use of near‐infrared spectroscopy (NIRS) and galvanic skin response (GSR). In essence if the a region of the brain becomes more active during a painful experience more oxygen will be extracted during that time. By using auscultation of heart rate with a stethoscope as a control procedure which should not elicit pain the authors were able to compare in a controlled fashion 28 newborns undergoing both activities. The use of NIRS was previously demonstrated as valid in the paper Pain activates cortical areas in the preterm newborn brain. Galvanic skin response has also been demonstrated to correlate with pain and measures changes in skin conductance in the paper Skin conductance compared to a combined behavioural and physiological pain measure in newborn infants. So the authors set out to compare findings in these 28 infants and standardized the study as much as they could by having one Neonatologist perform all hip exams and having a video recording of the infant’s face during the procedure assessed by two independent reviewers in order to assign the PIPP-R scores. While not a randomized trial, for the type of intervention being studied this was the right approach to take to determine the answer to their question. The Findings Interesting findings indeed. Statistically significant differences were noted in bilateral changes in oxygen extraction during hip examination as well as for the GSR small peaks. The PIPP-R scores as well were vastly different between the two groups suggesting that the areas of the brain responsible for perception of pain were indeed activated more so with manipulation of the hip than with auscultation of the heart. What can we take from this? The hip exam may elicit responses indicating pain but there remains the question of how much is actually elicited. Nonetheless, the authors findings are intriguing as they certainly challenge the notion that this is a quick exam that should be just done and gotten over with. Clearly bundling or Kangaroo Care are not an option here due to the nature of what is being done. The next time you are planning on doing such tests though should you at least consider non-nutritive sucking on a pacifier or sucrose solution if readily available? If not readily available then should it be?

Oral immune therapy (OIT) has really taken off at least in our units. The notion here is that provision of small amounts (0.2 mL intrabucally q2or 24 hours) can prime the immune system. Lymphoid tissue present in the oropharynx and intestine exposed to this liquid gold in theory will give the immune system a boost and increase levels of IgA. Such rises in IgA could help improve the mucosal defence barrier and therefore lessen the incidence of late onset sepsis. Rodriguez et al described this in their paper Oropharyngeal administration of colostrum to extremely low birth weight infants: theoretical perspectives in 2009. They followed it up the next year with a pilot study demonstrating how to actually administer such therapy. The fact that this approach has been adopted so quickly I think speaks to the principle that this kind of therapy falls into the category of “can’t hurt and might help”. The real question though is does it actually make a difference? Recently, authors from Brazil presented their findings from a single centre double blind RCT entitled Randomized Controlled Trial of Oropharyngeal Colostrum Administration in Very-low-birth-weight Preterm Infants. This authors are commended for studying this practice in such a fashion and included infants <34 weeks who were <1500g at birth to receive the above mentioned intervention. These infants were compared to placebo who received the same intervention except instead of mother’s own colostrum they were given sterile water. In total there were 149 infants randomized with 81 receiving OIT vs 68 who received a placebo. The primary outcome of interest on which a power calculation was performed was the incidence of late onset sepsis. Other typical outcomes including NEC, ROP, BPD, IVH and death were also followed. Did they find a difference? Sadly to many of you I am sure they did not as is shown in the table below. Surprisingly the authors also looked at levels of IgA in infants in both arms and also found no difference. There is a big problem with this study however that no doubt will lead to a repeat version at some point. While the authors enrolled the numbers above, the numbers that were analyzed in the table are 34 lower in the OIT arm and only 2 lower in the placebo group. In essence, a large number of mothers after enrollment were not able to provide the colostrum that was needed for the study. The study called for 48 applications over a 48 hour period and a little more than half of the mothers were able to do it. Do not be dismayed then that no difference was found here. There is no need to “throw the baby out with the bathwater” and abandon OIT based on this one study. I think what is needed in the future though is a study that enrolls far more than needed to account for attrition due to loss of mothers who can complete the study. Without another study I think the practice will continue but does it really make a difference to rates of sepsis? Who knows but there is no doubt it helps parents who are feeling that they have lost control of a pregnancy that has gone wrong, a positive experience and the feeling that they are doing something for their child.