AllThingsNeonatal

I had the pleasure of meeting the author of a paper I am about to comment on this week while at the 99 NICU conference in Stockholm. Dr. Ohlin from Orebro University in Sweden presented very interesting work on their unit’s “scrub the hub” campaign. As he pointed out, many places attempt to reduce coagulase negative staphylococcal infections by introducing central line bundles but seldom is there one thing that is changed in a bundle that allows for a before and after comparison like his team was able to do. I was so impressed by this work and at the same time concerned about another strategy to reduce infection that I felt compelled to make a comment here. Scrub the hub! Dr. Ohlin and the first author Dr. Bjorkman published Scrubbing the hub of intravenous catheters with an alcohol wipe for 15 sec reduced neonatal sepsis back in 2015. They compared a 16.5 month period in their unit when they rolled out a CLABI reduction bundle to a period of 8.5 months afterwards when they made one change. Nurses as is done in the units I work in were commonly scrubbing the hub before they injected the line with a medication but in the second epoch the standard changed to be a specified 15 second scrub instead of being left up to the individual nurse. With permission from Dr. Ohlin here is a picture of the hubs highlighting bacterial growth without scrubbing, then for a duration less than 15 seconds and then with 15 seconds. In the first epoch they had 9 confirmed CLABSIs and 0 confirmed in the second after their intervention. The rate of CLABSI then in the first epoch was 1.5% vs 0% in the second group. As with any study looking at sepsis, definitions are important and while they didn’t do paired cultures to rule out contamination (one positive and one negative as is the definition in our hospitals) they did refer each patient to a senior Neonatologist to help determine whether each case should be considered a true positive or not. Given that they made no changes to practice or other definitions in diagnosing infections during that time perhaps the results were indeed real. Presumably if they had missed an infection and not treated it in the second epoch the patient would have declared themselves so I think it is reasonable to say that 8.5 months without a CLABSI after their intervention is a success. As Dr. Ohlin points out the scrub duration may also help due to the abrasion of the hub surface removing a bacterial film. Regardless of the reason, perhaps a 15 second scrub is a good idea for all? The lazy person’s solution – the SwabCap One way to get around human nature or people being distracted might be to cover each luer lock with a cap containing 70% isopropyl alcohol. In this way when you go to access the line there should be no bacteria or labour required to scrub anything since the entry of the line is bathed in alcohol already. This was the subject of a systematic review from the Netherlands entitled Antiseptic barrier cap effective in reducing central line-associated bloodstream infections: A systematic review and meta-analysis. The reviews ultimately examined 9 articles that met their inclusion criteria and found the following; use of the antiseptic barrier cap was effective in reducing CLABSIs (IRR = 0.59, 95% CI = 0.45–0.77, P < 0.001). Moreover, they concluded that this was an intervention worth adding to central-line maintenance bundles. Having said that, the studies were mostly adult and therefore the question of whether minute quantities of isopropyl alcohol might be injected with medications was not a concern when they made their conclusion. What about using such caps in ELBW infants Sauron et al in St. Justine Hospital in Montreal chose to look at these caps more carefully after they were implemented in their NICU. The reason for taking a look at them was due to several luer valves malfunctioning. The authors created an in-vitro model to answer this question by creating a closed system in which they could put a cap on the end of a line with a luer lock and then inject a flush, followed by a simulated medication (saline) and then a flush and collect the injected materials in a glass vial that was sealed to prevent evaporative loss of any isopropyl alcohol. They further estimated the safe amount of isopropyl alcohol from Pediatric studies would be 1% of the critical threshold of this alcohol and using a 500g infant’s volume of distribution came up with a threshold of 14 mmol/L. The study then compared using the SwabCap over two different valve leur lock systems they had in their units (SmartSite and CARESITE valves) vs. using the strategy of “scrub the hub”. The results were quite concerning and are shown below. Circuit Type Temperature Sample 1 Sample 2 Sample 3 Mean SwabCap on Smart Site Valve Room 49.5 58.4 46.8 51.6 Incubator 35 degrees 45.16 94.7 77.9 72.6 SwabCap on CARESITE valve Room 14.1 5.7 5.2 8.34 Incubator 35 degrees 7.0 8.1 5.9 7.0 Isopropyl alcohol pad on CARESITE Valve Room 0 0 0 0 Certainly, the Smart Site valve allowed considerable amounts of isopropyl alcohol to enter the line but the CARESITE while better still allowed entry compared to the control arm which allowed none. Beyond the introduction of the alcohol into the system in all cases considerable clouding of the valves occurred with repeated capping of the system with new caps as was done with each med injection since each was single use. In lines that were not accessed contact with the cap was left for 96 hours as per recommendations from the manufacturer and these changes occurred as well. Conclusion While a reduction in CLABSI is something we all need to strive to obtain, it is better to take the more difficult path and “scrub the hub” and by that for 15 seconds which incidentally is the same recommended duration for hand hygiene in both of our units. Perhaps in larger term infant’s seepage of isopropyl alcohol into the lines would not be as concerning as their larger volume of distribution would lead to lower levels but I would ask the question “should any isopropyl alcohol be injected into any baby?”. I think not and perhaps by reading this post you will ask the same thing if your unit is using these caps. Thank you to Örebro University Hospital for their permission in using the photo for the post

Look around you. Technology is increasingly becoming pervasive in our everyday lives both at home and at work. The promise of technology in the home is to make our lives easier. Automating tasks such as when the lights turn on or what music plays while you eat dinner (all scripted) are offered by several competitors. In the workplace, technology offers hopes of reducing medical error and thereby enhancing safety and accuracy of patient care. The electronic health record while being a nuisance to some does offer protection against incorrect order writing since the algorithms embedded in the software warn you any time you stray. What follows is a bit of a story if you will of an emerging technology that has caught my eye and starts like many tales as a creative idea for one purpose that may actually have benefits in other situations. Meet Stethocloud In 2012 students in Australia rose to the challenge and designed a digital stethoscope that could be paired with a smartphone. The stethoscope was able to send the audio it was receiving to the smartphone for analysis and provide an interpretation. The goal here was to help diagnose childhood pneumonia with a stethoscope that would be affordable to the masses, even “Dr. Mom” as the following video documents. Imagine before calling your health line in your city having this $20 tool in your hands that had already told you your child had breath sounds compatible with pneumonia. Might help with moving you up the triage queue in your local emergency department. Shifting the goal to helping with newborns Of course breath sounds are not the only audio captured in a stethoscope. Heart sounds are captured as well and the speed of the beats could offer another method of confirming the heart is actually beating. Now we have ECG, pulse oximetry, auscultation and palpation of the umbilical stump to utilize as well so why do you need another tool? It comes down to accuracy. When our own heart rates are running high, how confident are we in what we feel at the stump (is that our own pulse we are feeling?). In a review on measurement of HR by Phillipos E et al from Edmonton, Alberta, auscultation was found to take an average of 17 seconds to produce a number and in 1/3 of situations was incorrect. The error in many cases would have led to changes in management during resuscitation. Palpation of the umbilical cord is far worse. In one study “cord pulsations were impalpable at the time of assessment in 5 (19%) infants, and clinical assessment underestimated the ECG HR with a mean (SD) difference between auscultation and palpation and ECG HR of − 14 (21) and − 21 (21) beats min –1″. In another study, 55% of the time providers were incorrect when they thought the HR was under 100 BPM. This leaves the door open for something else. Might that something be the digital stethoscope? How does the digital stethoscope fare? Kevac AC et al decided to look at the use of the Stethocloud to measure HR after birth in infants >26 weeks gestational age at birth. The opted to use the ECG leads as the gold standard which arguably is the most accurate method we have for detecting HR. The good news was that the time to signal acquisition was pretty impressive. The median time to first heart rate with the stethoscope was 2 secs (IQR 1-7 seconds). In comparison the time for a pulse oximeter to pick up HR is variable but may be as long as one minute. In low perfusion states it may be even longer or unable to pick up a good signal. The bad news was the accuracy as shown in the Bland Altman plot. The tendency of the stethoscope was to underestimate the EKG HR by about 7 BPM. Two standard deviations though had it underestimate by almost 60 BPM or overestimate by about 50 BPM. For the purposes of resuscitation, this range is far to great. The mean is acceptable but the precision around that mean is to wide. The other issue noted was the frequent missing data from loss of contact with the patient. Could you imagine for example having a baby who has a heart rate of 50 by the stethoscope but by EKG 100? Big difference in approach, especially if you didn’t have EKG leads on to confirm. The authors note that the accuracy is not sufficient and felt that an improvement in the software algorithms might help. Another go at it So as suggested the same group after having a new version with improved software decided to go at it again. This time Gaertner VD et al restricted the study to term infants. Forty four infants went through the same process again with the stethoscope output being compared to EKG lead results. This time around the results are far more impressive. There was virtually no difference between the ECG and the stethoscope with a 95% confidence interval as shown in the graphs with A being for all recordings and B being those without crying (which would interfere with the acquiring of HR). A maximal difference of +/- 18 BPM for all infants is better than what one gets with auscultation or palpation in terms of accuracy and let’s not forget the 2 second acquisition time! Should you buy one? I think this story is evolving and it wouldn’t surprise me if we do see something like this in our future. It certainly removes the element of human error from measuring. It is faster to get a signal than even the time it takes to get your leads on. Where I think it may have a role though is for the patient who has truly no pulse. In such a case you can have an EKG HR but the patient could be in pulseless electrical activity. Typically in this case people struggle to feel a pulse with the accuracy being poor in such situations. Using a device that relies on an actual heart contraction to make a sound provides the team with real information. Concurrent with this technology is also the rise of point of care ultrasound which could look at actual cardiac contractions but this requires training that makes it less generalizable. Putting a stethoscope on a chest is something we all learn to do regardless of our training background. I think they could be on to something here but perhaps a little more evidence and in particular a study in the preterm infant would be helpful to demonstrate similar accuracy.

I don’t envy our nurses who care for babies withdrawing from various opiates and other substances. These assignments are definitely a challenge and require a great deal of patience and depending on the shrillness of an infant’s cry a good set of earplugs. Nonetheless we do our best with these infants to keep them calm and avoid as much stimulation as we can as we attempt to minimize the excitability of their nervous system. Over 40 years ago the Finnegan Neonatal Abstinence scoring system was developed to assist medical teams by providing as objective a system as possible to compare one infant to another and determine when and if a patient should be treated pharmacologically. Unfortunately there is a problem inherent with this scoring system. It is the same problem that exists when you don’t have a blinded research trial. Imagine you are caring for an infant and you were given no history about drug exposure. How might you score a patient like that compared to one in which you are told has been exposed to illicit substances? Your senses are heightened and moreover if you were told this baby is “withdrawing terribly” or “is awful at night” you are biased. How are you likely to score such a patient when they are “on the edge” of being counted as a 1 or a 0 in a category? I bet in many cases, especially if you haven’t taken care of many such patients you err on the side of caution and score them on the high side. It is human nature. When the possible outcome of failing to recognize a withdrawing patient is a seizure, no one wants to be on when it happens having their scoring questioned. Have a look at the scoring tool though. There is a lot of stuff in there to check off! What if it could be simpler? The ESC Tool In early May, news began to break of an abstract being presented at the Pediatric Academic Society meeting. The news story from the AAP can be found here. The ESC tool is a three question tool used to assess whether an infant requires treatment for withdrawal. E – Eat (is an infant is able to eat 1 or more ounce per feeding) S – Sleeping (sleep for an hour or longer undisturbed) C – Console (Be consoled in 10 minutes or less.) If all three criteria are met, the patient does not need treatment. If one or more criteria are not met the housestaff are notified and first non-pharmacologic and then pharmacologic means are employed if necessary to control symptoms. The authors did something quite interesting. They looked at 50 patients with 201 hospital days with prenatal exposures to opiates and applied the ESC criteria to guide treatment. Concurrently they captured the Finnegan scores but did not use them to guide treatment. The findings I hope you will agree are quite interesting! “FNASS scores indicated starting morphine in 30 infants (60%). Morphine was actually started on only 6 patients (12%) (p< 0.0001) based on the ESC approach. The FNASS led protocol directed initiating or increasing meds on 24.6% of days compared to 2.7% of days using the ESC approach (p< 0.0001). The FNASS approach directed that morphine was either not started or decreased on 65.8% of days compared with 94.4% of days using the ESC approach (p< 0.0001). There were no readmissions or reported adverse events. Pretty amazing but… The ESC approach greatly reduced the need for treatment and as the authors state there were no readmissions or reported adverse events. What we don’t know and will be needed I suspect before anyone will adopt this strategy (which I have to say again is so much simpler that current approaches) is how these children do in the long run. If the system is undertreating withdrawal, could we see downstream impacts of a “kinder and gentler” approach? One outcome that will be reported soon in the next month is length of stay. I am eagerly awaiting further results as I for one think that a simpler approach to these patients may be just what the doctor ordered. I think the nurses might thank us as well but we will see just how appropriate it is! The Abstract reporting these findings can be found below Novel Approach to Evaluating and Treating Infants with Neonatal Abstinence Syndrome

I have often said that if this came to pass as a mandatory requirement that I would make an announcement shortly thereafter that I was moving on to another career. I think people thought I was kidding but I can put in writing for all to see that I am serious! The subject has been discussed for some time as I can recall such talks with colleagues both in my current position and in other centres. The gist of the argument for staying in-house is that continuity is improved over that period and efficiency gained by avoiding handovers twice a day . How many times have you heard at signover that extubation will be considered for the following morning or to keep the status quo for another issue such as feeding until the next day. No doubt this is influenced by a new set of eyes being in the unit and a change in approach to being one of “putting out fires” overnight. The question then is whether having one Neonatologist there for 24 hours leads to better consistency and with it better outcomes. With respect to PICUs the AAP has previously recommended that 24 hour in-house coverage by an intensivist be the standard so should Neonatology follow suit? A Tale of Two Periods My friends in Calgary, Alberta underwent a change in practice in 2001 in which they transitioned from having an in-house model of Neonatologist coverage for 24 hours a day to one similar to our own centres where the Neonatologist after handover late afternoon could take call from home. An article hot off the presses entitled Twenty-Four hour in-house neonatologist coverage and long-term neurodevelopmental outcomes of preterm infants seeks to help answer this question. The team undertook a retrospective analysis of 387 infants born at < 28 weeks gestational age during the periods of 1998-2000 (24 hour period, N=179 infants) vs 2002 – 2004 (day coverage, N= 208 infants) with the goal of looking at the big picture being follow-up for developmental outcome at 3 years. This is an important outcome as one can look at lots of short term outcomes (which they also did) but in the end what matters most is whether the infants survive and if they do are they any different in the long term. As with any such study it is important to look at whether the infants in the two periods are comparable in terms of risk factors for adverse outcome. Some differences do exist that are worth noting. Increased risk factors in the 24 hour group Chorioamnionitis Maternal smoking Smaller birthweight (875 vs 922 g) Confirmed sepsis (23% vs 14%) Postnatal steroids (45% vs 8%) – but duration of ventilation longer in the day coverage group likely due to less postnatal steroids ( 31 vs 21 days) All of these factors would predict a worse outcome for these infants but in the end for the primary outcome of neurodevelopmental impairment there was no difference. Even after controlling for postnatal steroids, birth weight, sex and 5 minute apgar score there was still no difference. What might this mean? Looking at this with a glass is half full view one might say that with all of the factors above predicting worse outcome for infants, the fact that the groups are not different in outcome may mean that the 24 hour model does indeed confer a benefit. Maybe having a Neonatologist around the clock means that care is made that much better to offset the effect of these other risk factors? On the other hand another explanation could also be that the reason there is no difference is that the sample just isn’t big enough to show a difference. In other words the size of the study might be underpowered to find a difference in developmental outcome. One of the conclusions in this study is that the presence of a Neonatologist around the clock may have led to earlier extubation and account for the nearly 10 day difference in duration of ventilation. While I would love to believe that for personal reasons I don’t think we can ignore the fact that in the earlier epoch almost 50% of the babies received postnatal steroids compared to 8% in the later period. Postnatal steroids work and they do so by helping us get babies off ventilators. It is hard to ignore that point although I woudl like to take credit for such an achievement. For now it would appear that I don’t feel compelled to stay overnight in the hospital unless it is necessary due to patient condition necessitating me having my eye on the patient. I am not sure where our field will go in the future but for now I don’t see the evidence being there for a change in practice. With that I will retire to my bedroom while I am on call and get some rest (I hope).

Posted on May 7, 2017 by winnineo In our journey as Neonatologists and interdisciplinary teams we are forever seeking to rid or at least reduce the plague of BPD in the patients we care for. The PREMILOC trial was a double-blind, multicenter, randomized, placebo-controlled trial designed to test just that concept by introducing a low dose of hydrocortisone within 24 hours of birth. They enrolled infants born between 24 – 26+6 weeks of gestation and assigned them to receive either placebo or low-dose hydrocortisone 0.5mg/kg twice per day for 7 days, followed by 0.5 mg/kg per day for 3 days. The trial has been the subject of a previous post A Shocking Change in Position. Postnatal steroids for ALL microprems? Although the trial was stopped early due to financial concerns the authors demonstrated a 9% reduction in BPD using this strategy. The theory here in part is that the presence of hydrocortisone reduces inflammation and that this in turn may allow for better growth of lungs with time. Why Not Adopt The Results Based on These Fantastic Results? Steroids in preterm infants have a bad name. As discussed in previous posts on the topic the concern in all trials has been the potential impact of such medications on the developing brain. A nice summary of these concerns can be found in a paper in the CMAJ by the other “Canadian Neonatal Blogger” from 2001 in which he quoted the risk of cerebral palsy increasing from about 1 in 6 babies to 1 in 3 if babies born at < 28 weeks were exposed to postnatal steroids. Neurodevelopmental impairment overall would change from 1 in 4 to 1 in 3 if such exposure occurred. This paper and others expressing concerns over the effect of postnatal steroids led to a change in practice from more ubiquitous use to one restrained to only in those cases where the patient was nearing the end of all other options. This meant holding out for such therapy until such patients were at 90% or more O2 and on high mean airway pressures. Although not formally studied I was very concerned at the time with using this approach as I felt it was a “fait de complet” that they would either die or have significant developmental impairment should they survive due to the complications of having such severe BPD. It is critical to note though that the outcomes from these long term studies were in infants exposed to much longer courses of dexamethasone and at high doses that are used today. Over the years with the development of the DART protocol and other more gentle approaches to steroids we as a group relaxed and certainly rescue courses of lower dose steroids have crept into practice when patients seem to be “stuck” on the ventilator. Drumroll Please… The results of the PREMILOC follow-up study are now here and in short they look good. Patients were followed up at an average age of 22 months and included a medical history, anthropometric measures, respiratory status, standardized neurological examination based on specific definitions of disabilities, and quantitative neurodevelopmental assessment using the revised Brunet-L.zine (RBL) scale. Follow-up was 93% in the hydrocortisone and 90% in the placebo arm which is important as we need not worry about the missed patients influencing the results to a significant degree if they had been included. Although some post-hoc analyses were done what I am most interested in is the primary outcome which is shown below. There was no difference in either neurodevelopment overall or any of the subcategories. This provides a great deal of reassurance to those who provide steroids this way. There will be those however that argue the study is too small. While a larger study might be better able to address whether there is a small difference in outcome I don’t think we will see one anytime soon. It is one of the challenges we face in Neonatology. Unlike the adult world with studies of thousands of patients, due to the small number of patients born at <28 weeks it is always a challenge to recruit into such large volume trials. We can compare trials by doing meta analyses or systematic reviews and perhaps that is where we will head with this study although given that different steroids will have been used (thinking dexamethasone as in the DART study) this will always be left open to question. Is it worth it? I suppose the real question here is the following for a parent to consider. “Would you like your baby to receive hydrocortisone shortly after birth with a 7% reduction in the risk of BPD at 36 weeks bearing in mind that although we don’t think there is an impact on long term development we aren’t certain yet”. I guess to answer this question you need to think about the first part of the question. Is BPD at 36 weeks a good outcome to look at for benefit? The Canadian Neonatal Network has recently called for a rethink on this The New BPD That Matters. It turns out that it is 40 weeks and not 36 weeks that has the greatest prediction for respiratory morbidity after discharge. If you were to move the goal post to 40 weeks from 36 I strongly suspect one would see the 9% reduction in BPD as shown in the PREMILOC trial vanish. If that is the case, would a slightly earlier extubation time be enough to motivate families to take the plunge? Although I often cringe at the expression “more trials are needed”, I think at least a combination of studies to achieve greater confidence in outcome may be needed. Barring that, we might just have to sit tight and accept that while there may be a little bit to be gained with the use of the PREMILOC protocol it may just not be enough to be clinically warranted at this time. May want to wait for the next big thing to tackle BPD…

I think my first training in resuscitation began with the principles outlined in the NRP 3rd edition program. As we have moved through subsequent editions with the current edition being number 7, I can’t help but think about how many changes have occurred over that time. One such change has been the approach to using medications as part of a resuscitation. Gone are such things as calcium gluconate, naloxone and sodium bicarbonate but something that has stood the test of time is epinephrine. The dosing and recommendations for administering epinephrine have changed over time as well with the dose of endotracheal medication increasing from 0.01 to 0.03 and now to 0.05 – 0.1 mg/kg. While this dosing has increased, that of IV administration has remained the same at 0.01 to 0.03 mg/kg. The change in dosing for the ETT route was due to an increasing awareness that this route just isn’t as effective as IV. Having said that with only 0.1% of resuscitations requiring such support the experience with either route is fairly limited. What is the concern? Giving a medication directly via the IV route ensures the dose reaches the heart in the amount desired. In the case of ETT administration there are a few potential issues along the way. The first is that one needs to push the dose down the ETT and this presumes the ETT is actually in the trachea (could have become dislodged). Secondly, if the medication is sent to the lung what effect does the liquid component in the airways have in terms of dilution and distribution of the medication? Lastly, even if you get the epinephrine to the lung it must be picked up at the capillary level and then returned to the left side of the heart. In the absence of significant forward pulmonary blood flow this is not assured. What is the evidence? In terms of human clinical research it remains fairly limited. Barber published a retrospective review of 47 newborns who received epinephrine via the endotracheal route. The study Use and efficacy of endotracheal versus intravenous epinephrine during neonatal cardiopulmonary resuscitation in the delivery room found that spontaneous circulation was restored in 32% of this cohort. Following the first dose, a subsequent dose of intravenous epinephrine restored circulation in 77%. This study provided the first suggestion that the IV route may be better than endotracheal. Keep in mind though that this study was retrospective and as the authors conclude in the end, prospective studies are needed to confirm these findings. The question really is what is the likelihood of restoring circulation if the first dose is given IV? Eleven years later we have a second study that attempts to answer this question although once again it is retrospective. Efficacy of Intravenous and Endotracheal Epinephrine during NeonatalCardiopulmonary Resuscitation in the Delivery Room by Halling et al. This study really was designed to answer two questions. The study group looked at the period from July 2006 to July 2014. During this period the dose of IV epinephrine remained unchanged as per NRP recommendations but the dose of endotracheal epinephrine increased from 0.01 to 0.03 and then to 0.05 mg/kg endotracheally. The increase was in response to both NRP and site observations that the lower doses were not achieving the effect they were hoping for. The Results ETT epinephrine IV Epinephrine Number 30 20 Return of circulation 23 15 1 dose 6 4 2 dose 5 8 3 doses 9 0 4 doses 3 3 In the ETT group all doses except for 3 after the first dose were given as IV. There was no difference in the response rate over time suggesting that higher doses do not truly increase the chance of a better response. The authors noted that the effectiveness of the two arms were not that different despite a significantly higher dose of epinephrine being administered to the group receiving ETT epinephrine first which is not surprising given the higher recommended dosages. What I find interesting though is that giving the first dose of epinephrine was given IV in 20 of the paitents, if it is indeed the better route one might expect a better response than in the ETT group. The response from one dose of ETT epi was 20% while that from the IV first group was in fact also only 20%! We do indeed need to be careful here with small numbers but the results at least to me do not suggest strongly that giving IV epi first ensures success. What the study suggests to me is that two doses of epinephrine may be needed to restore circulation. If you choose to start with IV it certainly does not seem unwise but if you have any delays I don’t see any reason to avoid ETT epinephrine as your first line. The reality is that for many individuals a UVC is a procedure that while they may have learned in an NRP class they may have never actually placed one. Having an ETT in place though seems like a good place to start. I doubt we will ever see a randomized trial of ETT vs IV epinephrine in Neonatology at this point given the stance by the NRP so these sorts of studies I suspect will be the best we get. For now, based on what is out there I suggest use the route that you can get first but expect to need additional doses at least one more time to achieve success. Lastly remember that even if you do everything correct there will be some that cannot be brought back. Rest assured though that if the first dose was given via ETT you have still done your best if that was the route you had.

The human body truly is a wondrous thing. Molecules made from one organ, tissue or cell can have far reaching effects as the products take their journey throughout the body. As a medical student I remember well the many lectures on the kidney. How one organ could control elimination of waste, regulate salt and water metabolism, blood pressure and RBC counts was truly thought provoking. At the turn of the century (last one and not 1999 – 2000) Medical school was about a year in length and as the pool of knowledge grew was expanded into the three or four year program that now exists. Where will we be in another 100 years as new findings add to the ever growing volume of data that we need to process? A good example of the hidden duties of a molecule is erythropoetin (Epo) the same one responsible from stimulating red blood cell production. Double Duty Molecule In saying that I am simplifying it as there are likely many processes this one hormone influences in the body but I would like to focus on its potential role in neuroprotection. In 1999 Bernaudin Et al performed an animal study in mice to test this hypothesis. In this elegant study, strokes were induced in mice and the amount of Epo and Epo receptors measured in injured tissues. Levels of both increased in the following way “endothelial cells (1 day), microglia/macrophage-like cells (3 days), and reactive astrocytes (7 days after occlusion)”. To test the hypothesis that the tissues were trying to protect themselves the authors then administered recombinant human Epo (rhEpo) to mice prior to inducing stroke and the injury was clearly reduced. This established Epo as a potential neuroprotectant. Other animal studies then followed demonstrating similar findings. A Human Trial When you think about hypoxic ischemic encephalopathy (HIE) you can’t help but think of whole body cooling. The evidence is pretty clear at this point that cooling in this setting reduces the combined outcome of death or neurodevelopmental disability at 18 months with a number needed to treat of 7. The risk reduction is about 25% compared to not those not cooled so in other words there is room to improve. Roughly 30-40% of infants who are cooled with moderate to severe HIE will still have this outome which leaves room for improvement. This was the motivation behind a trial called High-Dose Erythropoietin and Hypothermia for Hypoxic-Ischemic Encephalopathy: A Phase II Trial. This was a small trial comparing 50 patients (24 treated with rhEpo and cooling to 26 given placebo) who were treated with 1000 U of rEpo on days 1,2,3,5 and 7. Primary outcome was neurodevelopment at 12 months assessed by the Alberta Infant Motor Scale (AIMS)and Warner Initial Developmental Evaluation. A significant improvement in a subset of mobility on the latter was found and a significant difference in the AIMS overall. An additional finding giving support for a difference was that blinded reviews of MRI scans demonstrated a singificant improvement in brain tissue in those who received rhEPO. One curious finding in this study was that the mean timing of administration of rhEPO was 16.5 hours of life. Knowing that the benefit of cooling is best when done before 6 hours of age one can only wonder what impact earlier administration of a neuroprotective agent might have. This suggests that the addition of rEPO to cooling has additional impact but of course being a small study further research is needed to corroborate these findings. The Next Step This past week Malla et al published an interesting paper to add to the pool of knowledge in this area; Erythropoietin monotherapy in perinatal asphyxia with moderate to severe encephalopathy: a randomized placebo-controlled trial. This study was done from the perspective of asking if rhEPO by itself in resource poor settings without access to cooling in and of itself could make a difference in outcome for patients with HIE. This was a larger study with 100 Hundred term neonates (37 weeks or greater) with moderate or severe HIE. Fifty were randomized by random permuted block algorithm to receive either rhEPO 500 U kg− 1 per dose IV on alternate days for a total of five doses with the first dose given by 6 h of age (treatment group) or 2 ml of normal saline (50 neonates) similarly for a total of five doses (placebo group) in a double-blind study. The primary outcome was combined end point of death or moderate or severe disability at mean age of 19 months and the results of this and other important outcomes are shown below. Outcome Treatment Placebo p Death/disability (mod/severe HIE) 40% 70% 0.003 Death/disability (mod HIE only) 21% 61% 0.004 Cerebral Palsy 23% 45% 0.04 MRI abnormalities 40% 60% 0.04 Seizures treatment at 19 months 19% 43% 0.03 To say that these results are impressive is an understatement. The results are on par with those of cooling’s effect on reduction of injury and improvement in outcome. When looking at the primary outcome alone the result in dramatic when put in perspective of looking at number needed to treat which is 4! This is significant and I can’t help but wonder if the impact of this medication is at least in part related to starting the dosing within the same window of effectiveness of therapeutic hypothermia. Importantly there were no adverse effects noted in the study and given that rhEpo has been used to treat anemia of prematurity in many studies and not found to be associated with any significant side effects I would say this is a fairly safe therapy to use in this setting. Next Steps I find this puts us in a challenging position. The academic purists out there will call for larger and well designed studies to test the combination of rhEPO and cooling both initiated within 6 hours of age. While it takes years to get these results might we be missing an opportunity to enhance our outcomes with this combination that is right in front of us. The medication in question other than raising your RBC count has little if any side effects especially when given for such a short duration and by itself and possibly with cooling increases the rate of neuroprotection already. I don’t know about you but I at least will be bringing this forward as a question for my team. The fundamental question is “can we afford to wait?”

This post rings in another new video to add to the series on the All Things Neonatal YouTube channel. I hope that you have gotten something out of the ones posted so far and that this adds something further to your approach to neonatal care. The Golden Hour Revisited In the last post to the video selections the main thrust of the video was on the use of the Golden Hour approach to starting a baby on CPAP. Having a standardized checklist based approach to providing care to high risk newborns improves team functioning for sure. What do you do though when you need to hand off a patient to another team? Depending on where you work this may not be an issue if the team performing the resuscitation is the team providing the care for the patient in the NICU. Perhaps you work in a centre similar to our own where the team performing resuscitation is not the same as the one who will ultimately admit the patient. You may also be in a location where there are no babies born on site but rather all patients are transferred in so in each case the patient is new to everyone on the receiving team. How do you ensure that a complete hand over is done. Out with the old and in with the new! By no means do I want to imply that it is not possible to transfer information outside of the way that we demonstrate in this video. What I do believe though is that with telehealth being available in more and more settings or without a formal support for the same, the use of smartphones make video conferencing a reality for almost everyone. In most centres handovers have followed the practice of like communicating with like. Nurses give report to nurses, respiratory therapists to each other and MDs to MDs. What if there was another way though? In the video below we demonstrate another approach. Would it work for your team? As you can tell I am a big fan of simulation in helping to create high functioning teams! More of these videos can be accessed on my Youtube channel at All Things Neonatal YouTube To receive regular updates as new videos are added feel free to subscribe! Lastly a big thank you to NS, RH and GS without whom none of this would have been possible!

A debate broke out recently at one of our rounds when someone asked whether a recent case of NEC was possibly related to a transfusion that a baby received. Much has been written about Transfusion Associated Necrotizing Enterocolitis (TANEC) with the pendulum swinging back and forth between it existing as a real entity or simply being an association that is not causative in the least. Using one of my favourite sources, a retrospective analysis of the Canadian Neonatal Network database found no difference in mortality or morbidities for those who had a transfusion and NEC vs those without. Despite this we continue to see those who “hold feeds” for a few hours prior to transfusion and then resume them a few hours later. Why does this happen? Risk vs Benefit Those who hold feeds argue that in Neonatology we hold feeds for far less. Furthermore, what is the harm? If a baby develops NEC within 24 hours of a transfusion and we held the feeds we feel we have done all we could. If a baby is fed and develops NEC we are left asking “what if?”. The purists out there would argue the contrary though, that the evidence is not strong enough to support the practice and may require the insertion of an IV which is a painful procedure and places the infant at risk of infection from one or more skin breaks. Additionally, does the interruption of feeds potentially alter the microbiome of the patient and with it risk potential downstream consequences. In case you are wondering, I have tended to sit on the side of holding a feed although more often when I am asked about it than ordering it upfront. The fact is I just don’t know. The evidence has never been solid in this regard but it is hard to ignore the possibility when you have been bitten once or twice before (whether it was causative or not!). I doubt it really exists but then again what if there is something there? It May Not Be The Transfusion But Anemia Itself A recent paper Association of Red Blood Cell Transfusion, Anemia, and Necrotizing Enterocolitis in Very Low-Birth-Weight Infants may have found a possible explanation to the ongoing debate. Research papers associating transfusions with NEC may all have one thing in common in that they have not been able to prove causation. When you have many papers finding the same thing it leads medical teams to begin to believe there is causation. Something else may be at play at this paper suggests another association which again may not be causative but at least in my mind is perhaps biologically plausible. It may be that those patients who are transfused when their hemoglobin is below a threshold of 80 g/L are at increased risk of developing NEC rather than all patients transfused. This study was a secondary analysis of a prospective study on transfusion transmission of cytomegalovirus in preterm infants < 1500g. The authors chose 80 g/L as a cutoff based on previous studies suggesting this threshold as an important one for transfusion practices. Forty eight out of 60 eligible infants developed NEC and it is from this 48 that multivariable analysis sought to identify factors predisposing to the outcome in question of NEC. The factor with the greatest hazard risk for NEC was severe anemia in a given week with an approximate 6 fold risk (range 2 – 18) while receiving an RBC transfusion in a given week of life did not meet statistical significance. What does this mean? Before embracing the result and concluding we have the answer we have to acknowledge the authors have gone on a fishing expedition of sorts. Any secondary analysis of a study that is done carries with it some words of warning. There may be variables that were not controlled for that are affecting the results. As well when looking at many many variables it could be by chance that something or several things come up by chance. Lastly it may be that again there is nothing more than an association here at play. Having said that, there is some biologic plausibility at least here. Delivery of oxygen to the tissues is dependent on HgB level. The oxygen content of blood is described by: O2 content = (gm Hbg)(1.34 ml O2/gm Hbg)(% sat) + 0.003(pO2) = ml O2/dL. Oxygen delivery = cardiac output X O2 concentration (or content) Could RBCs become less deformable and increase viscosity in low O2 environments? This could be the case when the HgB declines below 80 g/L. Such changes to deformability have been demonstrated at mild levels of hypoxia as might exist in low pO2 conditions at the tissue level with anemia. So imagine we have fewer RBCs carrying as much oxygen as they can but eventually you cross a threshold where there is not enough O2 being delivered at the tissue level and the RBCs become lodged or perhaps sluggish as they move through capillaries of the intestines. Add to this that NEC occurs in watershed areas most commonly and you have the potential setup for NEC. Can we use the results of this study? I suppose statistical purists out there will argue that it is merely an association. The fact remains that there are many people who are holding feeds for varying amounts of time despite the lack of conclusive evidence that TANEC exists. I wonder if a middle ground might be to be more cautious and restrict such practice to those with low HgB values below 80 g/L as the authors here have found. To me at least there is biologic plausibility as outlined above. It would seem to me that to hold feeds for all babies is excessive and likely without evidence but could the threshold actually matter which it comes to oxygen content. Given that NEC is a condition related to ischemia, the authors here have provided another association that makes me at the very least scratch my head.

I have written about respectful communication before in Kill them with kindness. The importance of collaborating in a respectful manner cannot be overemphasized, as a calm and well prepared team can handle just about anything thrown their way. This past week I finally had the opportunity to take the 7th ed NRP instructor course. What struck me most about the new version of the course was not the approach to the actual resuscitation but the preparation that was emphasized before you even start! It only takes 30 seconds to establish who is doing what in a resuscitation and while it would seem logical to divide up the roles each will take on it is something that has not been consistently done (at least in our institution). When a baby is born and responds to PPV quickly, this may not seem that important but in a situation where a team is performing chest compressions, placing an emergency UVC and moving on to epinephrine administration it certainly is nice to know in advance who is doing what. The Golden Hour We and many other centres have adopted this approach to resuscitation and at least here developed a checklist to ensure that everyone is prepared for a high risk delivery. While teams may think they have all the bases covered, when heart rates are racing it may surprise you to see how many times crucial bits of information or planning is missed. As I told you in another post I will be releasing a series of videos that I hope others will find useful. The video in this case is of a team readying itself for the delivery of a preterm infant that they anticipate will have respiratory distress. Ask yourself as you watch the film whether your team is preparing to this degree or not. Preparing in such a fashion certainly reduces the risk of errors caused by assumptions about who is doing what or what risk factors are present. As you can tell I am a big fan of simulation in helping to create high functioning teams! More of these videos can be accessed on my Youtube channel at All Things Neonatal YouTube To receive regular updates as new videos are added feel free to subscribe! Lastly a big thank you to NS, RH and GS without whom none of this would have been possible!

The rise of donor milk banks and depots in recent years has been a welcome addition to the care of preterm infants. We have known for many years that “breast is best” and advocate for mother’s own milk whenever possible. When this is not possible we previously turned to formula but with the availability of pooled pasteurized donor milk many hospitals have focused on expanding the indications for use. Through personal communications in Canada we are a bit all over the map in terms of indications with some centres restricting use based on birth weight while others taking into account, gestational age as the main criteria. With respect to duration some centres use 2 weeks, others 4 and then others until a gestational age is reached which may mean up to 10 weeks of use for a baby born in that centre at 24 weeks. While variation exists it is hard to find anyone who would suggest this is a bad thing to provide. The main reason for pushing expansion of programs is the strong evidence that avoidance of bovine milk is associated with a reduction in the risk of NEC. Many studies have been done in this regard and the Cochrane systematic review concluded that formula increased the risk of necrotising enterocolitis: typical risk ratio 2.77 (95% CI 1.40 to 5.46); risk difference 0.04 (95% CI 0.02 to 0.07). While donor milk is a wonderful nutritional product for sure it does have one issue which is a lower protein content than mother’s own milk and as such dieticians will commonly increase the protein content from 0.9 g/dL to 1.2 g/dL by adding powder or more recently liquid protein supplements. One might expect then that doing so would provide a reduction is NEC, and an optimal source of nutrition for the growing preterm brain. Avoidance of NEC should reduce the risk of adverse neurodevelopmental outcome as the two have been linked before. Enter the DOMINO Study This Ontario, Canada based study utilized four NICUs to provide in a randomized fashion either donor human milk or formula with matching protein and caloric densities to 363 infants (181 donor milk, 182 formula). All infants were preferentially fed mother’s own milk but supplemented with donor or formula if unavailable and planned to use one or the other for up to 90 days or discharge whichever came first. The exposure to donor milk was quite long in comparison to our own units practice (1 month duration if born at < 1500g) . The median number of days for donor milk was 65 (IQR, 41-90). A significant risk to the results would be if there was a difference in amounts of mother’s own milk provided between the two groups but there was none. Exclusive feeding of mother’s own milk occurred in the Donor milk group (28.2%) and formula group (26.9%) respectively. Among infants requiring a supplement, there was no statistically significant difference between the donor milk and formula groups in the proportion of total enteral feeds for each infant consumed as mother’s milk (58.4% [IQR, 13.6%-96.0%] vs 63.3% [IQR, 9.6%-97.2%], respectively, P = .96). Short term but not long term gains Curiously (at least to me) I would have expected differences in some of the morbidities other than NEC but such was not the case. The strength of using human milk though can not be understated as any reduction in NEC is an extremely important outcome regardless of whether long term neurodevelopment is affected positively or not. in terms of the latter outcome no difference was observed between the two groups. The Bayley III findings were quite similar at 18 months which on the surface may cause everyone’s shoulders to sag as the benefit everyone hoped for did not transpire. Additionally, linear growth, head circumference and weight gain were not different between groups. This may simply reflect that protein and caloric intakes were indeed matched between groups whereas in the past, the lack of protein fortification led to delays in growth in the donor milk groups. At the risk of sounding like the end of a Cochrane review I am not sure this is the final word on donor milk and outcome. Larger studies may be needed to get at the real truth. This was not a pure sample of donor milk vs formula as a significant percentage (over 20% in both groups) received purely mother’s own milk. Furthermore, in those that received supplements there was still a significant percentage that received some of mother’s own milk. The authors suggest that a larger sample size would unlikely have detected a difference and that may be the case but is it so due to where the study was done. What if the study were done in a centre with a very low rate of breastfeeding? I am concerned that the lack of response in outcome may reflect a dilution of the impact of the strategy by having such a successful rate of providing mother’s own milk. All Is Not Lost Using a glass is half full view, I think it is worth pointing out that this study should also provide some comfort for those centres that use formula as a supplement. Clearly the higher rate of NEC is not comforting to anyone but for those who survive to discharge the neurodevelopmental outcome is promising. Formula in some circles has taken on a view as almost a toxic substance but I often remind residents and fellows that while we prefer breast milk, formula has been used in NICUs for decades and not every patient who receives it will develop NEC. Yes it is a risk factor for NEC and when you don’t have an alternative it is an acceptable form of nutrition to use. What I think may be lost in the DOMINO study is that if you are a centre that uses formula as there is no access to DBM this should help provide reassurance to the families you care for. All is not lost after the DOMINO study. Every cloud has a silver lining and fear not this will not be the last study to test this hypothesis. At the moment it is just the best we have and this is not the last we will hear on this topic.

Rather excited this week as Biomed Central picked up a blog post that I wrote on social media. The post is found here. It is based though on a larger version that I have included below and really delves into the impact of social media and how one uses it. A big thank you to Kristy Wittmeier for all of her help in writing the post. Original Piece I read with great interest the article by Campbell et al entitled Social media use by physicians: a qualitative study of the new frontier of medicine. The study interviewed 17 physician users of social media of which only one writer of a blog responded, but then declined to participate. The four themes that emerged of Rugged Individualism, Uncertainty, Social Media as Media and Time Constraints certainly resonate with me as a blogger who also happens to be a Pediatrician but more specifically a Neonatologist. The first theme truly resonates with me as I think back over the journey that has taken me to where I am now. We in the medical social media world are certainly learning as we go. Without clear paths drawn for us we explore and contemplate how we will make a positive difference far beyond the reach of the typical physician in a clinic, hospital or local community. The commentary that follows explores the journey that I have taken with social media; engaging in largely unpaid work to bring information to others using these forums. My own story as a Neonatal Blogger began in 2015 when my Minecraft-obsessed son asked me to help him start a blog about Minecraft. Two very poorly read posts started my foray into blogging using WordPress as my blogging forum. Around the same time, our family acquired a puppy and despite our best efforts over the next 18 months this new addition woke me between 4 – 5 AM daily. After being awoken one morning at 4 AM I read an article on NICU size as it relates to outcomes and had a marked reaction to the conclusions of the paper. On a whim on this early February morning, I chose to set up my own blog site, and All Things Neonatal was born. I would like to say that there was a master plan at the inception but it was due to a visceral reaction to a paper perhaps enhanced by irritability and fatigue that led to me choosing to put my thoughts out there. And I was hooked. A year and a half later, I have produced a total of 139 publications on the site. Knowing the benefit that I have received, and hopefully also imparted by engaging in social media as a healthcare professional has sparked my interest in encouraging others to consider doing the same. And for those interested in going beyond considering to doing, I would like to share some key learnings from my journey to inform yours. To establish yourself in the realm of social media you need to utilize more than one platform, obtain your content in a time efficient manner and do not let your voice stay silent for too long. Harnessing the combined power of multiple social media sites When you begin blogging you come to realize that the method has its limitations in terms of reach. As the paper suggests, the polling of social media users identifies multiple potential websites for both collecting and disseminating information (Facebook, Twitter, Tumblr, Linkedin, Google+ as examples). Using them in combination can far enhance your reach. At the time of this writing the number of people who “follow” me on each site is quite disparate with Facebook by far leading the way in distribution power. Table 1 – Variance in impact of commonly used social media websites Site Number of Followers Facebook 11859 Twitter 921 WordPress (my primary blogging platform) 393 Also in the article, concern is raised over the lack of feedback for social media users as it pertains to to data on interaction with their postings. With Facebook one cannot determine what was done with your post but on twitterthere is some further delineation as one receives a tally of impressions, engagements and link clicks. When it comes to real metrics though, this is where the actual blogging site provides more useful data. I recommend embracing metrics, not only to understand your reach but perhaps just as importantly to give you the drive to continue your writings. My most popular post, has received 5117 reads, meaning that this many took the time to open my blog post to hear what I had to say on the subject. If you were to share your thoughts on an article with colleagues via email, post a new guideline in an office or clinic or publish an article in a journal, how many people would actually see it? The same information, if cited in a blog post and shared through Facebook can see a dramatic rise in exposure, along with your interpretation of the work. The aforementioned post for example has had a reach on Facebook of 50934 people to date and was shared 58 times multiplying the distribution many fold. If you published a journal article and were notified of such circulation I suspect you would be jubilant. How to obtain content? One of the greatest benefits to my own practice has been the necessity of using a wide net to capture potentially interesting content for my readers. This habit facilitates the necessary practice of continuous learning through collecting articles from such sources as weekly automated pubmed searches, and various Child Health news websites. With time as your audience builds, postings on your own sites, tags on Facebook or mentions on Twitter draw your attention to content which your followers believe may be of interest to you. Remember in most circumstances you are not being paid for these efforts and in between managing the rest of your workday and balancing the demands of a personal life this aspect of your life needs to be done in a very time efficient manner. Do Not Let Your Voice Stay Silent For Too Long If you want people to pay attention to what you are adding to the pool of knowledge, deposits must occur frequently. Your followers are far more likely to mention you on various social media sites if they know you are likely to see and occasionally respond to their posts. Without such a presence, the mentions, likes and shares slow, as will your growth and relevance in the social media world. Future research should determine what the optimal frequency of posts to maximize reach would be. I have long suspected that excessive posting may have the effect of diluting the important messages while posting too infrequently means you may be quickly forgotten. Individuals must find the balance that works for them to keep their audience engaged while maintaining their motivation to continue the practice. What Really Motivates Those Who Participate in Social Media? I believe the motivation lies in the three qualities described by Malcolm Gladwell in his book The Tipping Point. He described three types of people that are needed for something to go from an idea to widespread adoption; connectors, mavens and salesmen. The doctors out there on social media likely have a little bit of all these characteristics. Gladwell said this about connectors; “They are people who “link us up with the world…people with a special gift for bringing the world together”. With respect to mavens he characterized them as having the ability to “start “word-of-mouth epidemics” due to their knowledge, social skills, and ability to communicate”. Lastly, salesmen in his view are “persuaders”. These three traits aptly describe those that have waded into this field. They must have the confidence to put their message out there with content that captures people’s attention and certainly have the goal of persuading people that it is worth considering what they have to say. The fundamental drive though comes from a place of harnessing these traits to help people. Whether writing original content or sharing what others have produced, the social media physician’s goal is generally pure and that is to share knowledge and generate discussion. For example, if you have a new strategy for reducing infection, the active social media physician would ask “why not share this with the world” rather than limit it to your institution or city. This frontier like field though does come with some caveats before you dip your feet into the collective pool of the various media sites. As opposed to the more traditional medium of peer reviewed publications there is no one to assess your content prior to its release. You are your own editor and therefore may miss the mark from time to time by missing a relevant publication that might influence your conclusions. You must be prepared for the good and the bad. One can easily appreciate the positive comments that often come but not all posts will be “home runs” and on some occasions the feedback (which will be public) may not be what you had hoped for. You must constantly reflect on your own potential biases yet strive to improve base of knowledge; adding more ‘signal’ than ‘noise’. Respect for patient confidentiality is paramount and within Canada and elsewhere. Organizations such as the Canadian Medical Association have set guidelines for conduct in this space that should be adhered to. [Ref 3] This new frontier for the Rugged Individualist is therefore not for the faint of heart. It does however bring the world closer together and provide one with a post-publication form of peer review. Once you enter into the fray it may surprise you how much information is in fact out there, that now flows to you through global connections. It is an evolving form of communication and one that I am happy to part of. In fact, I am a better neonatologist for it. Is it right for you?

The infant car seat challenge(ICSC) is a test which most definitely fits the definition of a battleground issue in Neonatology. After publishing the Canadian Pediatric Practice point on the same topic I received interesting feedback through the various social media forums that I frequent. While some were celebrating the consensus of the statement as verification that a centres’ non practice of the test was acceptable, others seriously questioned the validity of the position. The naysayers would point out that extremely infrequent events unless intentionally tracked may be difficult to pick up. In the case of the ICSC, if a few patients were to suffer a hypoxic event leading to an ALTE or worse after discharge, could the ICSC have picked out these babies and prevented the outcome? The evidence for adverse events associated with the use of car seats as discussed in the position statement is poor when using autopsy records over decades but when many clinicians can point to a failed ICSC picking up events, the thought goes that they “caught one”. Does catching one make a difference though? The Well Appearing Infant Shah et al in their recent paper Clinical Outcomes Associated with a Failed Infant Car Seat Challenge attempt to address this very point. They performed a retrospective study of 148 patients who were either <37 weeks GA or < 2500g at birth. The study was made possible by the fact that all such infants in their hospital admitted to a well newborn area meeting these criteria by policy must have an ICSC prior to discharge. Keep in mind that these were all infants who were on the well newborn service since they were asymptomatic. The definition of an event in this group was one or more of pulse oximeter saturation ≤ 85% for > 10 seconds, apnea > 20 seconds, bradycardia < 80 bpm for > 10 seconds, or an apnea or bradycardia event requiring stimulation. The failure rate was 4.5% which is very similar to other reported studies. Why did they “fail”? Failure of the ICSC was owing to desaturation 59% Bradycardia 37% Tachypnea 4% Combination of 2 in 11% What is interesting about these results is what happened to these infants after admission to the NICU in that 39% were identified with apnea (48% in preterm vs 17% in term infants). These events were in the supine position which is a curious finding since the ICSC was designed to find risk of cardiorespiratory stability in a semi-recumbent position. This has been shown previously though. What does it all mean? The infants in this study ultimately had more NG feeding, prolonged length of stay and septic workups after failing the ICSC that comparable infants who passed. At first blush one would read this article and immediately question the validity of the CPS position but then the real question is what has this added to the “pool of knowledge”. That infants may fail an ICSC at a rate of 4.5% is already known. That such infants may demonstrate apneic events has also been shown before and a study like this may help to support those clinicians who feel it is still imperative to find these infants in order to achieve a safe discharge. I think it is important to put these findings in the context of what would have happened if such a unit did not routinely test these types of babies. As all were seemingly well and I presume feeding with their families, they would have been discharged after 24-48 hours to home. We have no evidence (since they have not compared this sample to a group who did not have such testing) that if these babies were discharged they would have faired poorly. The supporters of the ICSC would point to all the support these babies received by admitting them for 6-8 days, providing NG feeding and ruling out sepsis that they were unsafe for discharge. The other possible way to look at it was that the infants were subjected to interventions that we have no evidence helped them. Whether any of these infants had a positive blood culture justifying antibiotics or needed methylxanthine support is not mentioned. Judging however by the short length of stay I suspect that none or few of these infants needed such medication as I would expect they would have stayed much longer had they needed medical treatment for apnea. Conclusion I do commend the authors for completing the study and while it does raise some eyebrows, I don’t see it changing at least my position on the ICSC. While they have described a cohort of patients who failed the ICSC nicely, the fundamental question has been left unanswered. Does any of this matter? If you look well, are feeding well and free of any clinically recognizable events but are late preterm or IUGR can the ICSC prevent harm? This has not been answered here and perhaps the next step would be for a centre that has abandoned the ICSC to follow their patients after discharge prospectively and see whether any adverse outcomes do indeed occur. Any takers?

As a Neonatologist I doubt there are many topics discussed over coffee more than BPD. It is our metric by which we tend to judge our performance as a team and centre possibly more than any other. This shouldn't be that surprising. The dawn of Neonatology was exemplified by the development of ventilators capable of allowing those with RDS to have a chance at survival. As John F Kennedy discovered when his son Patrick was born at 34 weeks, without such technology available there just wasn't much that one could do. As premature survival became more and more common and the gestational age at which this was possible younger and younger survivors began to emerge. These survivors had a condition with Northway described in 1967 as classical BPD. This fibrocystic disease which would cripple infants gave way with modern ventilation to the "new bpd". The New BPD The disease has changed to one where many factors such as oxygen and chorioamnionitis combine to cause arrest of alveolar development along with abnormal branching and thickening of the pulmonary vasculature to create insufficient air/blood interfaces +/- pulmonary hypertension. This new form is prevalent in units across the world and generally appears as hazy lungs minus the cystic change for the most part seen previously. Defining when to diagnose BPD has been a challenge. Is it oxygen at 28 days, 36 weeks PMA, x-ray compatible change or something else? The 2000 NIH workshop on this topic created a new approach to defining BPD which underwent validation towards predicting downstream pulmonary morbidity in follow-up in 2005. That was over a decade ago and the question is whether this remains relevant today. Benchmarking I don't wish to make light of the need to track our rates of BPD but at times I have found myself asking "is this really important?" There are a number of reasons for saying this. A baby who comes off oxygen at 36 weeks and 1 day is classified as having BPD while the baby who comes off at 35 6/7 does not. Are they really that different? Is it BPD that is keeping our smallest babies in hospital these days? For the most part no. Even after they come off oxygen and other supports it is often the need to establish feeding or adequate weight prior to discharge that delays things these days. Given that many of our smallest infants also have apnea long past 36 weeks PMA we have all seen babies who are free of oxygen at 38 weeks who continue to have events that keep them in hospital. In short while we need to be careful to minimize lung injury and the consequences that may follow the same, does it matter if a baby comes off O2 at 36, 37 or 38 weeks if they aren't being discharged due to apnea or feeding issues? It does matter for benchmarking purposes as one unit will use this marker to compare themselves against another in terms of performance. Is there something more though that we can hope to obtain? When does BPD matter? The real goal in preventing BPD or at least minimizing respiratory morbidity of any kind is to ensure that after discharge from the NICU we are sending out the healthiest babies we can into the community. Does a baby at 36 weeks and one day free of O2 and other support have a high risk of coming back to the hospital after discharge or might it be that those that are even older when they free of such treatments may be worse off after discharge. The longer it takes to come off support one would think, the more fragile you might be. This was the goal of an important study just published entitled Revisiting the Definition of Bronchopulmonary Dysplasia: Effect of Changing Panoply of Respiratory Support for Preterm Neonates. This work is yet another contribution to the pool of knowledge from the Canadian Neonatal Network. In short this was a retrospective cohort study of 1503 babies born at <29 weeks GA who were assessed at 18-21 months of age. The outcomes were serious respiratory morbidity defined as one of: (1) 3 or more rehospitalizations after NICU discharge owing to respiratory problems (infectious or noninfectious); (2) having a tracheostomy (3) using respiratory monitoring or support devices at home such as an apnea monitor or pulse oximeter (4) being on home oxygen or continuous positive airway pressure at the time of assessment While neurosensory impairment being one of: (1) moderate to severe cerebral palsy (Gross Motor Function Classification System ≥3) (2) severe developmental delay (Bayley Scales of Infant and Toddler Development Third Edition [Bayley III] composite score <70 in either cognitive, language, or motor domains) 3) hearing aid or cochlear implant use (4) bilateral severe visual impairment What did they find? The authors looked at 6 definitions of BPD and applied examined how predictive they were of these two outcomes. The combination of oxygen and/or respiratory support at 36 weeks PMA had the greatest capacity to predict this composite outcome. It was the secondary analysis though that peaked my interest. Once the authors identified the best predictor of adverse outcome they sought to examine the same combination of respiratory support and/oxygen at gestational ages from 34 -44 weeks PMA. The question here was whether the use of an arbitrary time point of 36 weeks is actually the best number to use when looking at these longer term outcomes. Great for benchmarking but is it great for predicting outcome? It turns out the point in time with the greatest likelihood of predicting occurrence of serious respiratory morbidity is 40 weeks and not 36 weeks. Curiously, beyond 40 weeks it becomes less predictive. With respect to neurosensory impairment there is no real difference at any gestational age from 34-44 weeks PMA. From the perspective of what we tell parents these results have some significance. If they are to be believed (and this is a very large sample) then the infant who remains on O2 at 37 weeks but is off by 38 or 39 weeks will likely fair better than the baby who remains on O2 or support at 40 weeks. It also means that the risk of neurosensory impairment is largely set in place if the infant born at < 29 weeks remains on O2 or support beyond 33 weeks. Should this surprise us? Maybe not. A baby who is on such support for over 5 weeks is sick and as a result the damage to the developing brain from O2 free radical damage and/or exposure to chorioamnionitis or sepsis is done. It will be interesting to see how this study shapes the way we think about BPD. From a neurosensory standpoint striving to remove the need for support by 34 weeks may be a goal worth striving for. Failure to do so though may mean that we at least have some time to reduce the risk of serious respiratory morbidity after discharge. Thank you to the CNN for putting out what I am sure will be a much discussed paper in the months to come.

Positive pressure ventilation puts infants at risk of developing chronic lung disease (CLD). Chronic lung disease in turn has been linked many times over, as a risk for long term impacts on development. So if one could reduce the amount of positive pressure breaths administered to a neonate over the course of their hospital stay, that should reduce the risk of CLD and by extension developmental impairment. At least that is the theory. Around the start of my career in Neonatology one publication that carried a lot of weight in academic circles was the Randomized Trial of Permissive Hypercapnia in Preterm Infants which randomized 49 surfactant treated infants to either a low (35-45) or high (45-55) PCO2 target with the thought being that allowing for a higher pCO2 should mean that lower settings can be used. Lower settings on a ventilator would lead to less lung damage and therefore less CLD and in turn better outcomes. The study in question did show that the primary outcome was indeed different with almost a 75% reduction in days of ventilation and with that the era of permissive hypercapnia was born. The Cochrane Weigh in In 2001 a systematic review including this and another study concluded that there was insufficient evidence to support the strategy in terms of a benefit to death or chronic lung disease. Despite this lack of evidence and a recommendation from the Cochrane group that permissive hypercapnia be used only in the context of well designed trials the practice persisted and does so to this day in many places. A little lost in this discussion is that while the end point above was not different there may still be a benefit of shorter term ventilation. A modern cohort It would be unwise to ignore at this point that the babies of the late 90s are different that the ones in the current era. Surfactant and antenatal steroid use are much more prevalent now. Ventilation strategies have shifted to volume as opposed to pressure modes in many centres with a shift to early use of modalities such as high frequency ventilation to spare infants the potential harm of either baro or volutrauma. Back in 2015 the results of the PHELBI trial were reported Permissive hypercapnia in extremely low birthweight infants (PHELBI): a randomised controlled multicentre trial. This large trial of 359 patients randomized to a high or low target pCO2 again failed to show any difference in outcomes in terms of the big ones “death or BPD, mortality alone, ROP, or severe IVH”. What was interesting about this study was that they did not pick one unified target for pCO2 but rather set different targets as time went on reflecting that with time HCO3 rises so what matters more is maintaining a minimum pH rather than targeting a pCO2 alone which als0 reflects at least our own centre’s practice. There is a fly in the ointment here though and that is that the control group has a fault (at least in my eyes) Day of life Low Target High Target 1-3 40-50 55-65 4-6 45-55 60-70 7-14 50-60 65-75 In the original studies of permissive hypercapnia the comparison was of a persistent attempt to keep normal pCO2 vs allowing the pCO2 to drift higher. Although I may get some argument on this point, what was done in this study was to compare two permissive hypercapnia ranges to each other. If it is generally accepted that a normal pCO2 is 35-45 mmHg then none of these ranges in the low target were that at all. How did these babies do in the long run? The two year follow-up for this study was published in the last month; Neurodevelopmental outcomes of extremely low birthweight infants randomised to different PCO2 targets: the PHELBI follow-up study. At the risk of sounding repetitive the results of Bayley III developmental testing found no benefit to developmental outcome. So what can we say? There is no difference between two strategies of permissive hypercapnia with one using a higher and the other a lower threshold for pCO2. It doesn’t however address the issue well of whether targeting a normal pCO2 is better or worse although the authors conclude that it is the short term outcomes of shorter number of days on ventilation that may matter the most. The Truth is Out There I want to believe that permissive hypercapnia makes a difference. I have been using the strategy for 15 or so years already and I would like to think it wasn’t poor strategy. I continue to think it makes sense but have to admit that the impact for the average baby is likely not what it once was. Except for the smallest of infants many babies these days born at 27 or more weeks of gestation due to the benefits of antenatal steroids, surfactant and modern ventilation techniques spend few hours to days on the ventilator. Meanwhile the number of factors such chorioamniotitis, early and late onset sepsis and genetic predisposition affect the risks for CLD to a great degree in the modern era. Not that they weren’t at play before but their influence in a period of more gentle ventilation may have a greater impact now. That so many factors contribute to the development of CLD the actual effect of permissive hypercapnia may in fact not be what it once was. What is not disputed though is that the amount of time on a ventilator when needed is less when the strategy is used. Let us not discount the impact of that benefit as ask any parent if that outcome is of importance to them and you will have your answer. So has permissive hypercapnia failed to deliver? The answer in terms of the long term outcomes that hospitals use to benchmark against one and other may be yes. The answer from the perspective of the baby and family and at least this Neonatologist is no.