AllThingsNeonatal

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.

Neurally adjusted ventilatory assistance or NAVA is something that has been around for awhile. Available as a mode on the Maquet ventilator it uses an esophageal probe to sense myoelectrical activity in the diaphragm and provide assistance with postive pressure when detected. This is supposed to be better than the more traditional Graseby capsules or sensing based on airflow. Conceptually then if a preterm infant had a typical mixed apneic event with a component of both central and obstructive apnea this technology could sense an attempt to breath and assist the infant with positive pressure when the diaphragm indicates it is time for a breath. Such support should work to maintain functional residual capacity. A better ventilated lung could lead to less systemic oxygen desaturation and bradycardia correct? Retrospective review in Virginia Tabacaru CR et al just published NAVA—synchronized compared to nonsynchronized noninvasive ventilation for apnea, bradycardia, and desaturation events in VLBW infants. This is a retrospective study and non randomized looking at a single centres experience in 108 VLBW infants in which the attending providers were free to choose the type of respiratory support infants received after extubation. The authors from this group examined 61 epochs of time on niNAVA compared to 103 for the non invasive positive pressue ventilation nIPPV group. niNAVA patients received an initial level (the factor by which the electric diaphragmatic signal intensity (edi) is multiplied) of 1.0 and a PEEP of 5 to 6 cm H2O. NIPPV was initiated at a positive inspiratory prrssure (PI)P of 14 to 16 cm H2O, PEEP of 5 to 6 cm H2O and a rate of 20 breaths per minute. Adjustments were dictated by oxygenation and blood gases and were not described as protocolized but rather left up to clinicians. All events were recorded manually by nursing. What impact did niNAVA have on apnea and bradycardia? There were no significant differences noted between the two study groups including such important parameters as birthweight, day of life of extubation, sepsis or whether they needed to be reintubated. All of these could be markers of worse lungs in one group or the other so at least them seem pretty much the same. What about the effect on apnea and bradycardia? The bold numbers in the table indicate that only the number of bradycardias per day differed between the groups. Whether patients desaturation events or not was not affected. Also not effected was whether or not patients had apnea. Why might these results make sense? First off since the study was not randomized and is small there is always the possibility that these results are not real and occurred just by chance. There could be variables for example that we are not taking into account to explain why some patients were chosen for one modality or the other than affect the outcomes here. Having said that let’s look at the three outcomes. Apnea – why would this be different at all? Both modalities provide support when needed. If the infant decides to stop breathing I would see the lack of neural output not being affected by either modality so perhaps if the primary issue is lack of respiratory drive for most we wouldn’t expect a difference. Desaturation – if pulmonary reserve is kept about the same with both approaches it seems reasonable that we might not see a difference here either. Bradycardia – here there was a difference. Can this be explained as something plausible. I think there might be something here. Use of NAVA just might have a faster and more accurate response time than nIPPV that relies on airflow. Due to leaks around the prongs or mask it is possible that while background pressures are relatively maintained, not all needed positive pressure helping breaths are received in as timely a fashion as when they are detected via electrical activity. The ability of niNAVA to help the infant overcome the obstructive component of breathing might be reason why bradycardia is reduced. The interruption of ventilation is briefer with less reflexive bradycardia. What is needed of course next is a randomized prospective controlled trial. Who knows when that will come but for the infants that we see with seeminly methylxanthine resistant apnea might niNAVA be the path to avoiding reintubations? Time will tell

Glucose metabolism in the newborn can be a tricky thing to manage. Neonates can have significant fluctuation in their serum glucose in the first few days of life which can lead heels to look like pin cushions. How many times have you been asked as a physician if there is anything we can do to reduce the number of pokes? That something may have arrived at least in a feasibility study that could pave the way for this becoming the standard approach to hypo/hyperglycemia in the newborn. This is an important area to improve tightness of control as hyperglycemia has been associated in VLBW infants with such adverse outcomes as IVH, ROP and NEC. Continuous glucose monitoring (CGM) with closed loop insulin delivery The principle here is that a meter is inserted subcutaneously that detects blood glucose fluctuations and responds by either increasing infusion of dextrose for low glucose or delivery of insulin. The technology has been around for some time and used in the adult population but is relatively new in this population. I have written about it before in Continuous glucose monitoring in NICU may be around the corner. What follows is the latest pilot study to test this out coupled with glucose or insulin delivery in a closed loop system. The study in this case is out of Cambridge in the UK and entitled Feasibility of automated insulin delivery guided by continuous glucose monitoring in preterm infants . What did they do? The study was a pilot of 20 patients randomized to have an automated system to regulate glucose based on CGM data from 48-72 hours of age vs a paper based algorithm to manage dextrose or insulin infusion rates during the same period. The sample size was one of convenience to test the concept and the period was chosen to allow for time to recruit patients. The sensor used was an Enlite attached to a laptop with software capable of delivering infusion rates to two alaris pumps (one with 20% dextrose and the other with insulin). Target serum glucose levels were set to be between 4-8 mmol/L. The babies included were all under 1200g and had mean weights of 962g in the closed loop and 823g in the control arm. The Results were fairly dramatic in my mind at least. A remarkable 91% of the infants in the closed loop system had glucose levels in the target range vs 26% in the control arm. Nutritional intakes and mean insulin dosing were not any different between groups. No harm in addition was noted from use of the CGMs. You don’t escape pokes all together though as the device does require q6h checks to calibrate and ensure it is reading properly. Every 6 hours is better though than every three for those with brittle control! The Benefit Tightly regulating blood glucose and avoiding both lows and highs has benefits on the low end to neurological preservation. On the high end some complications such as IVH, NEC and ROP may be avoided by better control. The challenge with the system as is at the moment is that it is not widely available. I am eager for a company out there to create software for mass distribution that would enable us to try this out. While the calibration is still required I can’t help but think this is an improvement over what we have at the moment. Stay tuned as I think this one is for real and will appear in NICUs sooner than you think!

The story around cord management after birth continues to be an evolving one. I have certainly posted my own thoughts on this before with my most recent post being Delayed cord clamping may get replaced. Time for physiological based cord clamping. While this piece demonstrated that there are benefits to longer times till clamping is done, it also showed that if you go too long hypothermia becomes a real risk and with it possible complications. At least in our centre the standard that we have tried to reach is DCC for one minute for our infants. As you will no doubt know from the literature reviewed here before, this is likely not long enough! One or Three Minutes? This study caught my eye this week. Effect of early versus delayed cord clamping in neonate on heart rate, breathing and oxygen saturation during first 10 minutes of birth – randomized clinical trial What struck me in particular about this paper was not just the physiologic outcomes it was looking at. What is remarkable is the size of the study. So many articles that are published in Neonatology have under a hundred patients. On occasion we see studies with hundreds. In this case the authors included 1510 patients who were randomized to early ≤60 s of birth and ≥ 180 s for time of clamping. What is also interesting here is that early which used to be considered right after delivery of the infant is now 1 minute in this study. I like that this is the accepted new norm for this type of study. Inclusion criteria were such that these were all low risk vaginal deliveries with fetal heart rate (FHR) ≥100 ≤ 160 bpm and all infants were ≥33 weeks. Although 1510 were randomized (power calculation for sample size found there should be 566 per group based on an expected loss of 25% per arm. In the end there were 670 in the ECC and 594 in the DCC groups that adhered to the protocol. In the ECC group the mean duration of time till clamping occurred was 31.2 s (+/-14.4) vs 198.5s (+/-16.9). The Results The goal after delivery is to increase blood flow to the lungs as PVR drops. In order to do so this requires adequate ventilation but it also requires adequate perfusion of the myocardium. If you clamp too early and pulmonary blood flow has not yet increased you run the risk of having a sudden drop in coronary blood flow with oxygenated blood from the placenta and with that bradycardia. A longer time on “heart lung bypass” from the placenta should allow for a smoother transition. That is what was seen here. At 1, 5 and 10 minutes infants randomized to the DCC had better oxygen saturations. Heart rates interestingly were lower in the DCC group but that could also be related to better oxygenation leading to less compensatory tachycardia. In other studies in which the cord was clamped immediately bradycardia was more common. This difference here may reflect timing of the clamp on heart rate. Lastly, time to first breath was much faster in the group randomized to DCC. Might this be an effect of better oxygenation? What they didn’t measure? There was no comment on risk of hypothermia or other markers of illness such as rates of admission to NICU, hypoglycemia, lethargy or other markers of an infant who became cold. If this is to become standard practice measures need to be in place to prevent these concerns from becoming reality. It is also worth noting the population studied. These are healthy late preterm and term pregnancies. More work is needed on younger infants and those with risk factors in pregnancy. How would mothers with poor tracings, diabetes or hypertension fare as well as those who have growth restricted infants? This field is growing and I will continue to follow this evolving story and share information as it becomes available. One thing in my mind is fairly certain though and that is that clamping right after delivery for routine births should be a thing of the past.

To be sure there are fans of both HFNC and CPAP out there. I have often heard from other Neonatologists that they use HFNC and find positive results while other centres refuse to use it in favour of the tried and true CPAP. Turning to the literature you will find some conflicting results with some studies suggesting equity and others more recently favouring CPAP. There has been speculation as to why one would be superior to the other and now we appear to have some answers as to where the differences lie. A Physiologic Study Liew et al published Physiological effects of high-flow nasal cannula therapy in preterm infants this month in an elegant study of 40 infants. The study was fairly simple in design either randomizing infants <37 weeks to starting with nCPAP +6 and then transitioning to 8 l/min HFNC followed by stepwise reductions of 1 l/min until 2 l/min was reached or the reverse, starting with 2 l/min and working their way up and then transitioning to nCPAP+6. All infants were on one or the other modality at the start and were all at least 3 days old, they were randomized to one or the other arm regardless of where they started off. Physiologic measurements were taken at each step including the following: Mv -Minute ventilation pEEP – nasopharyngeal end-expiratory pressure pEECO2 -nasopharyngeal end-expiratory CO2 RR – respiratory rate; SpO2 – oxygen saturation TCCO2 – transcutaneous CO2 Vt – tidal volume A Fabian device was used to deliver either HFNC or CPAP at the different flows for all patients. The Results The authors certainly found some interesting results that I think shed some light on why comparisons of HFNC and CPAP have been so inconsistent. Table 2 contains the results of the study and I will point out the main findings below. 1. Flow matters – Compared to nCPAP+6 which is fairly consistent flows below 6 l/min deliver pEEP that is below 6 cm H2O. 2. Keep the mouth shut – With CPAP whether the mouth is open or closed the Fabian device delivers +6 cm H2O. As you can see from the table, when the mouth is open transmitted pressures drop off substantially. The infant put on a flow of even 6-8 l/min of HFNC sees pressures less than +6 consistently. 3. As flows increase end expiratory CO2 decreases. HFNC seems to help wash out CO2 4. Low flow rates on HFNC do not seem to help with ventilation as much as higher flow rates. In order to maintain Mv these infants at 2 l/min flow become tachypneic. The low pressures produced likely cause some atelectasis and hence tachypnea. Size matters! Beware of excessive pressures. An additional finding of this study was that on “multiple linear regression, flow rate, mouth position, current weight and gestation but not prong-to-nares ratio significantly predicted pEEP and account for a significant amount of its variance (F(4431)=143.768, p<0.0001), R2=0.572, R2=adjusted 0.568).” Essentially, infants under 1000g in particular could see pEEP levels as high as 13 cm H2O with flows of 8 l/min. The variability in transmitted pressures with HFNC is shown nicely in this figure from the study. As flows increase above 6 l/min the actual pressures delivered become less reliable. Conclusions Looking at this data, it becomes evident why HFNC may be failing in its attempt to dethrone nCPAP. In order to achieve higher pressures and provide comparable distending pressure to nCPAP you need higher flows. With higher flows though come the problem of greater variability in delivered pressure. While the average pressure delivered may be equivalent or even higher than a CPAP of +6, in some infants (especially those below 1000g) one may be delivering significantly higher pressures than intended which may help with oxygenation and preventing intubation but others may be seeing far less than needed. What it comes down to is that nCPAP is better at delivering a consistent amount of pressure. Studies using lower flows of HFNC likely failed to show superiority to CPAP as they just didn’t deliver enough pressure. An example of this was the study by Roberts CT et al Nasal High-Flow Therapy for Primary Respiratory Support in Preterm Infants, in which flows of 6-8 l/min were used. Other studies using higher pressures could have been problematic due to open mouths, or larger babies not receiving as much benefit. I am not saying that we should throw out HFNC entirely however. Depending on the unit you practice in you might not be able to use CPAP but HFNC may be allowed. If you had to choose between no support or HFNC I would likely go with the HFNC. For me at least, if I want to delivery reliable pressures in my tertiary care NICU I will be calling for the CPAP.

I have written about non-traditional methods of providing surfactant to newborns previously. The practice of intubating a preterm infant to administer surfactant and leaving the endotracheal tube in with a slow wean of ventilation is mostly a thing of the past (at least in my units). Strategies have evolved and have seen the development of the INSURE technique, LISA methods, use of an LMA to delivery surfactant and even simple deposition into the pharynx all with variable success. The Holy Grail To me at least, the Holy Grail of surfactant delivery has been aerosolization. A small non randomized study was done in by Finer et al in 2010 An open label, pilot study of Aerosurf® combined with nCPAP to prevent RDS in preterm neonates. This study noted a reduction in CPAP failure with nebulized surfactant but as a pilot was not large enough to move the needle. Since then the Cochrane group weighed in and declared that there was not enough evidence to support the practice. The CureNeb group anchored by Dr. Pillow though has now published a double blind RCT entitled Nebulised surfactant to reduce severity of respiratory distress: a blinded, parallel, randomized controlled trial. It certainly sounds interesting and might help determine if the needle has indeed moved. The Study Poractant alfa at 200 mg/kg was used in this study and delivered via aerosolization using a vibrating membrane called the eFlow. The authors chose to look at infants from 29 0/7 to 33 6/7 weeks at birth and stratified them into two groups of 29 0/7 to 31 6/7 and 32 0/7 to 33 6/7 weeks. They estimated a need for 70 babies based on an anticipated failure rate of 30% in the control group vs 5% in the treatment group. Unfortunately, due to several reasons the study was only able to recruit 64 babies for randomization before being stopped due to the recruitment issues. The design of the study included adequate blinding with a sham procedure and there were predefined “failure criteria” necessitating intubation at the outset of the study. These criteria are acceptable to me as they are similar enough to my own practice and were: 1. FiO2 >0.35 over more than 30 min OR FiO2 >0.45 at anytime. 2. More than four apnoeas/hour OR two apnoeas requiring bag and mask ventilation. 3. Two capillary blood gas samples with a pH <7.2 and partial pressure of carbon dioxide >65 mm Hg (or partial pressure of carbon dioxide in arterial blood (PaCO2) >60 mm Hg if arterial blood gas sample). 4. Intubation deemed necessary by the attending physician. What did they find? The primary outcome CPAP failure within 72 hours of birth was indeed different in the two groups. CPAP failure by 72 hours CPAP + surfactant 11/32 (34%) CPAP 22/32 (69%) (RR (95% CI)=0.526 (0.292 to 0.950)) Clearly the event rates were quite off from what they expected in the power calculation but given that they found a difference as opposed to no difference at all the fact that they didn’t recruit the numbers they planned is of less importance. However, what is interesting is when they looked at the planned analysis by stratification an interesting finding emerged. Group 1 (29 0/7 to 31 6/7) CPAP failure by 72 hours CPAP + surfactant 12/21 (57%) CPAP 12/19 (63%) (RR (95% CI)=0.860 (0.389 to 1.90)) Group 2 (32 0/7 to 33 6/7 CPAP failure by 72 hours CPAP + surfactant 1/11 (9%) CPAP 10/13 (77%) (RR (95% CI)=0.254 (0.089 to 0.727)) There were a number of secondary outcomes looked at as well which may be of interest to you but as the numbers here are quite small I will not comment other than to say there was no increased incidence of complications with surfactant administration in this fashion. Also for those who ultimately failed CPAP the time when they did so was quite delayed compared to CPAP alone. Age at intubation for nCPAP failure, hours 4.9 (2.7–10.6) 11.6 (9.0–31.1) 0.008* What can we take from this? I believe these results are encouraging even if the study is a small one. The message I take from this study is that aerosolization of surfactant delivers some amount of product to the lungs. Those with more significant RDS or smaller lungs (those in the 29 0/7 to 31 6/7 group) may not get enough surfactant to treat their RDS sufficiently to avoid intubation. Those with less significant RDS or a larger number of alveoli get “enough” of a dose delivered to the alveoli to make a difference and avoid intubation. It is worth stressing that there can be no specific comment about using this strategy in even more immature infants as they weren’t tested. If I had to guess though, I would expect no difference given the findings in the smaller group. As a physician responsible for transport though I am interested in the potential benefits to those born in non-tertiary centres. Many centres lack individuals with the confidence and skill to regularly place endotracheal tubes. For these centres it may be that providing nebulized surfactant could delay the time to treatment failure, allowing more time for a trained transport team to arrive. Training of course would be needed in these centres on how to administer surfactant in this way but it is an interesting concept to consider. With a near tripling of the average time to treatment failure the extra hours on CPAP would be much appreciated when weather delays or difficulty securing air assets means long delays in transport team arrivals. To be sure this isn’t the last study of this kind but it certainly is an interesting start and one that will no doubt produce questions that will help formulate the next study design.

Just about all of our preterm infants born at <29 weeks start life out the same in terms of neurological injury. There are of course some infants who may have suffered ischemic injury in utero or an IVH but most are born with their story yet to be told. I think intuitively we have known for some time that the way we resuscitate matters. Establishing an FRC by inflating the lungs of these infants after delivery is a must but as the saying goes the devil is in the details. The Edmonton group led by Dr. Schmolzer has had several papers examined in these blogs and on this occasion I am reviewing an important paper that really is a follow-up study to a previous one looking at the impact of high tidal volume delivery after birth. I have written on this previous paper before in It's possibile! Resuscitation with volume ventilation after delivery. On this occasion the authors have published the following paper; Impact of delivered tidal volume on the occurrence of intraventricular haemorrhage in preterm infants during positive pressure ventilation in the delivery room.This observational study had a simple enough premise. Will the use of Vt > 6 mL/kg in infants given PPV for at least two minutes lead to worse rates of IVH? All infants were < 29 weeks and if they had chest compressions or epinephrine were excluded. All infants were treated equally in terms of delayed cord clamping and antenatal steroid provision. Ventilation was done with a t-piece resuscitator and Vt measured with an NM3 monitor connected to the face mask. First ultrasounds were done for all at 3 days of age. What did the authors find? One hundred and sixty five infants comprised this cohort. Overall, 124 (75%) infants were in the high volume group compared to 41 (25%) with a mean VT<6 mL/kg. Median Vt were 5.3 (4.6-5.7) ml/kg for the low group and 8.7(7.3-10.6) mL/kg which were significantly different. When looking at the rates of IVH and the severity of those affected the results are striking as shown in the table. Hydrocephalus, following IVH developed in 7/49 (14%) and 2/16 (13%) in the >6 mL/kg and <6 mL/kg VT groups. Looking at other factors that could affect the outcome of interest the authors noted the following physiologic findings. Oxygen saturations were lower in the low volume group at 6, 13 and 14 min after birth while tissue oxygenation as measured by NIRS was similarly lower at 7,8 and 25 min after birth (P<0.001). Conversely, heart rate was significantly lower in the VT>6 mL/kg group at 5, 20 and 25 min after birth (P<0.001). Fraction of inspired oxygen was similar in both groups within the first 30 min. Systolic, diastolic and mean blood pressure was similar between the groups. What these results say to me is that despite having lower oxygen saturations and cerebral oxygen saturation at various time points in the first 25 minutes of life the infants seem to be better off given that HR was lower in those given higher volumes despite similar FiO2. Rates of volume support after admission were slightly higher in the high volume group but inotrope usage appears to be not significantly different. Prophylactic indomethacin was used equally in the two cohorts. Thoughts for the future Once a preterm infant is admitted to the NICU we start volume targeted ventilation from the start. In the delivery room we may think that we do the same by putting such infants on a volume guarantee mode after intubation but the period prior to that is generally done with a bag and mask. Whether you use a t-piece resuscitator or an anesthesia bag or even a self inflating bag, you are using a pressure and hoping not to overdistend the alveoli. What I think this study demonstrates similar to the previous work by this group is that there is another way. If we are so concerned about volutrauma in the NICU then why should we feel any differently about the first few minutes of life. Impairment of venous return from the head is likely to account for a higher risk of IVH and while a larger study may be wished for, the results here are fairly dramatic. Turning the question around, one could ask if there is harm in using a volume targeted strategy in the delivery room? I think we would be hard pressed to say that keeping the volumes under 6 mL/kg is a bad idea. The challenge as I see it now is whether we rig up devices to accomplish this or do the large medical equipment providers develop an all in one system to accomplish this? I think the time has come to do so and will be first in line to try it out if there is a possibility to do a trial.

We have all been there. After an uneventful pregnancy a mother presents to the labour floor in active labour. The families world is turned upside down and she goes on to deliver an infant at 27 weeks. If the infant is well and receives minimal resuscitation and is on CPAP we provide reassurance and have an optimistic tone. If however their infant is born apneic and bradycardic and goes on to receive chest compressions +/- epinephrine what do we tell them? This infant obviously is much sicker after delivery and when the family asks you “will my baby be ok?” what do you tell them? It is a human tendency to want to reassure and support but if they ask you what the chances are of a good outcome it has always been hard to estimate. What many of us would default to is making an assumption that the need for CPR at a time when the brain is so fragile may lead to bleeding or ischemia would lead to worse outcomes. You would mostly be right. One study by Finer et al entitled Intact survival in extremely low birth weight infants after delivery room resuscitation.demonstrated that survival for infants under 750g was better if they had a history of CPR after delivery. The thought here is that more aggressive resusctiation might be responsible for the better outcome by I would presume establishing adequate circulation sooner even if the neonates did not appear to need it immediately. The Canadian Neonatal Network In Canada we are fortunate to have a wonderful network called the Canadian Neonatal Network. So many questions have been answered by examining this rich database of NICUs across the county. Using this database the following paper was just published by Dr. A. Lodha and others; Extensive cardiopulmonary resuscitation of preterm neonates at birth and mortality and developmental outcomes. The paper asked a very specific and answerable question from the database. For infants born at <29 weeks gestational age who require extensive resuscitation (chest compressions, epinephrine or both) what is the likelihood of survival and/or neurodevelopmental impairment (NDI) at 18-24 months of age vs those that did not undergo such resuscitation? For NDI, the authors used a fairly standard definition as “any cerebral palsy (GMFCS1), Bayley-III score <85 on one or more of the cognitive, motor or language composite scores, sensorineural or mixed hearing impairment or unilateral or bilateral visual impairment.” Their secondary outcomes were significant neurodevelopmental impairment (sNDI), mortality, a Bayley-III score of <85 on any one of the components (cognitive, language, motor), sensorineural or mixed hearing loss,or visual impairment.sNDI was defined as the presence of one or more of the following: cerebral palsy with GMFCS 3, Bayley-III cognitive, language or motor composite score <70, hearing impairment requiring hearing aids or cochlear implant, or bilateral visual impairment” What did they discover? It is a fortunate thing that the database is so large as when you are looking at something like this the number of infants requiring extensive resuscitation is expected to be small. The authors collected data from January 1, 2010 and September 30, 2011 and had a total number of infants born at less than 29 weeks of 2760. After excluding those with congenital anomalies and those who were born moribund they were left with 2587. From these 80% had follow-up data and when applying the final filter of extensive resuscitation they were left with 190 (9.2%) who received delivery room CPR (DR-CPR) vs 1545 who did not receive this. Before delving into the actual outcomes it is important to note that neonates who did not receive DR-CPR were more likely to be born to mothers with hypertension and to have received antenatal steroids (89 vs 75%). With these caveats it is pretty clear that as opposed to the earlier study showing better outcomes after DR-CPR this was not the case here. The results are interesting in that it is pretty clear that receiving DR-CPR is not without consequence (higher rate of seizures, severe neurological injury, BPD). Looking at the longer term outcomes though is where things get a little more interesting. Mortality and mortality or neurodevelopmental impairment are statistically significant with respect to increased risk. When you take out NDI alone however the CI crosses one and is no longer significant. Neither is CP for that matter with the only statistically significant difference being the Bayley-III Motor composite score <85. The fact that only this one finding came out as significant at least to me raises the possibility that this could have been brought about by chance. It would seem that while these infants are at risk of some serious issues their brains in the long run may be benefiting for the neurological plasticity that we know these infants have. The study is remarkable to me in that an infant can have such a difficult start to life yet hope may remain even after dealing with some of the trials and tribulations of the NICU. Parents may need to wade through the troubling times of seizures, long term ventilation and CPAP and then onto a diagosis of BPD but their brains may be ok after all. This is one of the reasons I love what I do!