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Hello, everyone. I'd like to think metal for asking me to speak today on advances in the management of bronchopulmonary dysplasia. I'm Dr Michael Gnarby. I mean, the only a tolerance to the University of Manitoba. And when it paid Canada, I'd like to begin with a quote from Steve Jobs. If you define the problem correctly, you almost have the solution. This is a really important quote for this talk, because we're going to be going through recommendations that are based on evidence and based on best practices that were found in Canadian and I see is to reduce bronchopulmonary dysplasia. The objectives are to provide a background on the Canadian landscape for neonatology. Secondly, to understand best practices towards reducing bpd. And thirdly, to review some of the evidence supporting these recommendations do the time constraints. We won't be able to go through all the evidence for the recommendations that support each point. But I will do my best to highlight the important pieces of evidence that support these. So I'd like to begin with discussing the Canadian Noon it'll network. This is a grouping of 32 I see use across Canada that was started in 1995. The purpose of the Canadian Yanal Network was to take a relatively small country of Canada with 37.6 million people as of today and group all the units together in order to get data that we could use to better the care for babies across the country. We know from the group ins of babies that we have. About 4% of all births in Canada will come through the and I see you. And if you come to the and I see the mortality rate is about 3% using 2019 data, the CNN had almost 15,000 babies of meditation. I see use. And as you can see when you get to the bottom of the lower figure, the number of babies under 33 weeks that we can look at across the country was 4446. This gives us the opportunity to use group numbers together to get great data and look at, for example, how one unit compares to another and to identify those units that have the best outcomes and then asking important question, which is why, to that end, they author Richard Pascal published some years ago, The power of positive deviance and the reason I selected this book to highlight here is because in Canada we have a program called Epic, which I will talk about in the next slide. The concept of epic is much like the examples outlined in the book. The power positive deviants was to look at places in the world that have had a problem, and that problem was overcome and not just overcome. But the effect of interventions were produced, the greatest reduction in the issue that they were trying to solve By looking critically at what those people have done and trying to replicate that another centers. You can apply the same or hope to get the same reductions and improve outcomes for whether it's the infectious illness or in the case that we're talking about. Improve outcomes for newborns so that end The evidence based practice for proving quality or ethnic group was spun off from the Canadian neonatal network many years ago. In the early two thousands in the first grouping of Epic one, there were 12 of the 32 sites that participated, and they looked at a couple of problems. One Waas nose, a communal infection and bronchitis. Pulmonary dysplasia, so seems, were dispatched to those centers in the Canadian, the own it'll network that had the best outcomes in these two areas. And the teams looked very critically at what those units were doing to achieve these low rates. Then they applied rigorous appraisals that evidence based on what they found the practice is where the different from other centers. And then the idea was to apply those changes and see if you could replicate those reductions in other centers. That, too, involved 25 out of 28 sites when the CNN was only 28 sites and looked at retinopathy, a prematurity nose, a coma infection, bpd neck and I V H. This was done over four years with the goal of improving each of these outcomes by determining what the best practices were to achieve improvements in Epic three, which is where we currently are. Based on epic one and two, there is there are units across the country that are extubated into an eye. PPV and others extubate into CPAP, and the outcomes of these infants are being examined in terms of successful extubation in terms of rates of ppd. Um, I should point out that well, this is a very systematic pds A or plan do study act, um, type of approach. Not every recommendation is adopted by all centers, and there may be locally in each center reasons for that not happening. But regardless, the purpose of coming up with bundles is to offer almost Iressa pee for various centers to see if they're outcomes are not good things that they could be doing that might improve to that end on. After the first two rounds of epic, Canadian researchers, along with those in other countries, decided to look at the outcomes for, uh, accomplish that outcome that I've mentioned previously. Things like retinopathy, a prematurity and nose accumulates sepsis with ppd. And then they looked at the trends from 17 4015, with and without bpd. I've highlighted in the upper right corner the Canadian You Nana Network, because what this showed Waas. Although the overall rate of the compass it outcome hovered around 20% during this time, there was a significant decline in the rate of the constant outcome, including bpd from 2007 to 2015, where it started at 45% and finished it about 30%. You do not see this across the other countries that are indicated in this paper from 2019. What this suggested was that the interventions that were put into place to reduce ppd helped actually reduce ppd. So when we're talking about BPH E, this is from the Canadian the A mental network, and we define bpd as needing some degree of respiratory supported 36 weeks post menstrual age. Not surprisingly, when you look at this report from the CNN, you find that under 25 weeks about 85% of babies will have ppd. That drops to about 70% of 25 to 26 weeks and so forth and so forth until you get to 31 32 weeks. When you're talking about approximately rate of 10% the ppd is divided into mild, which is being on, um, nasal prongs oxygen moderate, which is CPAP less than 30% and severe being either CPAP over 30% oxygen or being ventilated. And as you can see as the station legend creases the percentage of babies that have mild bpd increases as of the as the overall rate of bpd declines. But this means we have room for improvement. So let's go through the current bundle for bpd to see some of the recommendations and what we can do to perhaps improve the rates in your center if you're not doing some of these things. So in the delivery sweet uh, it's very clear that the use of non invasive risperidone resupport has improved at rates of ppd. As we've tried to rely more on the use of non invasive support instead of intubation, we have found the rates of DPT and 36 weeks decline. Some units abandoned noninvasive support after plus five or plus six centimeters of water. But those with the best outcomes are using up to plus seven plus eight for CPAP before going to intubate. And so that's something that we certainly have adopted in our center when you look at when to give oxygen. The recommendation, based on best outcome again, is somewhere between a minimum threshold of 0.3 f i 02. But certainly by the time you reach 20.5 f i 02. The time is there to give it. But the reality is we're not a static practice. There's always growth in the in Italia, lots of research. So the question is, Can we re fine? Who will get bpd? This was work done in our own center by one of our former fellows and my colleagues, in which we looked retrospectively at the use of lung ultrasound and whether lung ultrasound done and babies who were born into 29 weeks and we had 27 infants. If lung ultrasound was done between 2 to 8 weeks, could we identify a pattern? Could we find a threshold at which we could predict who would go on to develop chronic lung disease, which could be very useful for both parents in terms of anticipatory guidance, but also potentially implementing different strategies to try to reduce that risk of bpd if we know they're already higher risk? What we found was the median long ultrasound score was knowing versus three and those who had bpd versus those who did not. And in particular, if you look at the two receiver operator curves on the left, the one on the left is for all babies under 29 weeks. The one on the right was just under 27 weeks, and you saw under 27 weeks that the specificity and sensitivity are much higher. And what we found in this retrospective study was that a long ultrasound score over six predicted outcome of DPT. Now you can contrast this with a wreck with a prospective study that came out at the following year in 2019, in which the authors examined 38 patients without BVD versus 21 who ultimately develop ppd and, in a perspective fashion. They did lung ultrasounds that one on the first day, the third day and then weekly until the 28 then if they were stolen. I'm respiratory support every two weeks thereafter. What the authors found and that's showing the figure on the left is that the lung ultrasound scores and this probably won't surprise. You were definitely higher in those kids who develop ppd at all time points, um, with the exception at birth and, um, at three days. But after that they found that the uh, higher scores and the school threshold they found was a cut off of five we had found a cut off of greater than six. They found it cut off of five. But if you had a lung percents for that was five or above. This predicted that these infants would go on to develop chronic lung disease. The figure on the right demonstrates the sensitivity and specificity. Not surprisingly, the sensitivity. At 24 weeks, if you had a lung ultrasound score of five or more, um, predicted bpd with virtually 100% accuracy or was present, I should say Ah, 100% of the time in those that had ppd. But similarly, the sensitivity falls off dramatically at 32 weeks because those babies might have significant lung disease warranting a high level percent score. But they don't go on to develop ppd. But so we can you know. The bottom line is we can use long ultrasound, too. Inform our practice to perhaps look at earlier use of post nasal steroids if needed on predict which babies are much more likely to have a rougher course for the family. The next topic to discuss is that of minimally invasive surfactant treatment. This has come on the scene in the last few years, and in systematic reviews has been found to reduce the risk of bronchopulmonary dysplasia and survival with a drunk a pulmonary dysplasia compared to the tip. More typical, ensure. Yet a number of questions continue. Teo exist with this practice. One question is. Which baby should have a laryngoscopy and a catheter inserted in the trachea and surfactants and still versus having an intubation? If the point of doing this is to cause less airway trauma and toe lead to a less bpd, then certainly, as I mentioned in the previous couple slides, those infants at 32 weeks and above have a low likelihood of bpd. So should these babies have insure, or should they have missed? Typically in Canada, we're seeing most centers now that are doing it. And we know there's about a third of the centers now doing this, and most centers are, uh, using a cut point of between 26 to 30 weeks. The next question becomes which surfactant There are surfactants, which your dose to 2.5 mL per kilogram. Of those that air does 5 mL per kilogram. Research out of London, Ontario, in Canada has found that the volume of 5 mL per kilogram is a surfactant installation for MS has been, well tolerated. Eso I think the evidence would suggest it's really up to the center, which is a fact they're more comfortable with. And another hot topic, of course, is pre medication. Should you use pre medication with the inherent risk of apnea as a possibility? That is a consideration. But on the other hand, Laryngoscopy is uncomfortable. So should you not give them something? So this is still in area of research? Ah, hot topic has been a couple of things. One is the use of macrolide sets his is it through my son and patients who may be ureaplasma really a composite of and can we decrease inflammation lead to less, ppd. I think the jury is still out on that. There's no still not enough evidence convincingly that this makes a difference and therefore, for the time being, macrolides or not recommended. What is interesting, though, is a provision of prophylactic contra cortisone. The first, um, we or week and a half of life, um Teo give physiologic doses in order to prevent chronic lung disease. This has been a very long story that going back almost 20 to 25 years in which it was initially identified that babies who were adrenally insufficient, especially in the presence of Korea and I just could have higher risks of developing chronic lung disease. And so, um, about a year to year and a half ago, the study was published. It went in which the four studies, where individual patient data was still available, were all grouped together and an individual patient data. That analysis was performed, and you will see looking at all of the studies they all have in common that the babies were generally under 29 weeks. Uh, they were all double blind are CT's. All babies were under 1250 g. And in the most recent study, which is, uh, perhaps the better known study as of late, which is the priming lock study, it was a 10 day course of prophylactic hydrocortisone. All started within 12 hours are sorry before 20 out for 24 hours of age. The outcomes are quite fascinating. The survival without bpd if you give prophylactic contra cortisone overall was 53.3% versus 45.5% and that was statistically significant, which makes one thing that this is a worthwhile exercise. The challenge, though, with this therapy, is that when you look at Table six from the individual patient Med analysis, there's lots of questions that emerge. For example, the survival to 36 weeks without bpd was found to only be significant and females. Similarly, survival was only found to be significant without bpd if you were greater than or equal to 26 weeks. It may be that the reason for this is that the disadvantage when you're born under 26 weeks is so significant from pulmonary and maturity that the prophylactic after cortisone cannot overcome that. As with previous studies, the presence of Corioni an artist, uh, and treatment with prophylactic contra cortisone reduce the risk of chronic lung disease. Unfortunately, death before discharge was only positively affected by being born after greater than or equal to 26 weeks. And if you received prophylactic card, a cortisone with the presence of chorioamnionitis late onset sepsis, though under 26 weeks, was found to be increased, as was the presence of chorioamnionitis. And lastly, if you received indomethacin and prophylactic cadre cortisone that increase your risk of spontaneous intestinal perforations. You might look at these results and say that we should just throw out the idea of using prophylactic cortisone under 26 weeks. However, further research has shown significant beneficial effects in both MRI findings of the brain and neuro development in that group that received hot prophylactic contra cortisone under 26 weeks. So this is something that you can expect to see more work on, and I suspect much like we see in Canada, more and more units made pounds start to use this treatment. So look for that. Another thing that's been of interest lately is the recognition that is babies age preterm instance. If they may need higher title Williams now, can I call this the PICU approach here in Winnipeg, when we hear about babies who are quite chronic and that they may be going to PICU will often here are spiritually therapist mentioned that they'll use the PICU ventilation approach when they go there, which is difficult to use 5.5 to 6 mL per kilogram Now, this is the rationale for this is based on, um, an increase in an itch anatomical and of your dead space And what is the evidence for that? Marty Kessler, back in 2009, published this paper of 26 infants under 800 g of birth and using the practice of permissive hypertension targeting Oh, two's in the mid forties, initially and then up into the fifties as the weeks went by. What you can see is that the measure title of volume over time, was increasing. The XL, titled lines, were increasing up to about 6 mL per kilogram to maintain a normal so, too, and also you can see that many ventilation also needed to increase from the beginning of 2 87 meals per kilo, permitted up to 3 37 miles per kilo per minute to maintain a acceptable. So, too, what this suggests is that the very compliant preterm airway, maybe dilating not just in the distal lobby only, but also the trachea level of the bronchial level. And it is this increase in dilation of the airway that may be leading to increase dead space. So perhaps while we try not to use excessive volume over 5.5 or 5.5 or more in the initial steps of, um, an infant's life. Uh, once these babies or 2 to 3 weeks of age, perhaps we don't need to go to high frequency ventilation, but we could tolerate a higher. This type of work was augmented in 2019 by Katie Hunt when she looked at infants under 32 weeks who remained ventilated past a week of age. These infants were treated with randomly treated with 456 or seven miles per kilo of, um, volume for 20 minutes each. And she measured the work of breathing in these infants by the pressure time product of the diaphragm. The conclusion of this study was it was on leeway with the use of seven miles per kilo of title volume, that she could actually demonstrate a reduction work of breathing. And I would say anecdotally in the and I see you, we see this because as we go up on people, if we maintain that volume of 4 to 4 to 4.5 or five mils per kilo, we often see, even though we can get the f i 02 down, the nurses will comment. The babies that still have work of breathing. So is that what's really going on that they simply don't have enough volume. Additional recommendations are to extubate as early as clinically appropriate to minimize race of invest, base of intellect in. And I would add to that that no one should ever have 100% extra patient success rate is you're not trying enough. Another point is, do not use high flow nasal cannula, which has become very popular to transition from the intubated state to the Extubated state in particular under 28 weeks. And that be this study from 2020 looked at the effect of an open mouth. And when you compare babies who are pre term on CPAP of six and versus flows on high flow nasal cannula anywhere from 2 to 8 liters per minute, what you found was when the mouth was closed, you could get very decent pressure similar to the six centimeters of water pressure that you have set on CPAP. But with the mouth open do the leak even up to eight leaders a minute. You would only reach 5.1 centimeters of water pressure. So the bottom line is, if you're needing pressure after excavation, our recommendation here from Canada from the epic group would be to use CPAP, not high flow nasal cannula. And this was quite consistent in Canada that those centers that had greater uses of high flow nasal cannula have the highest rates of BBT. Last thing to mention is these of histograms. We used to extubate babies or to reduce CPAP based on our instinct is to what the F 02 was. But by taking data off the monitor and finding out the percentage of time babies are spending 95 above 90 95 so forth, uh, if you can aimed to be within the S P 02 alarm limits greater than 70% of the time before you either extubate or reduce CPAP, we find that that will offer the best chance of success for extra vacation, and it at we're reducing CPAP if again. If you reduce to quickly, you respect blame loss and then needing to really be re recruit lost volume, which sometimes means to reintabate, which can increase your risk of disease. And this was demonstrated in this paper from 2020 in which 36 infants under 30 weeks were perspective. Have perspective daily Histograms collected and what was found was you were far more likely to be put back on CPAP after having your CPAP discontinued. If you're histograms were worse. So you can see from this study the oxygen saturations and the different ranges were generally lower in those that failed cpap discontinuation in the 24 hours prior to being discontinued and better in those that had a shift to the right of their histograms. I like to say we practice what we preach, we've been rolled. We've adopted many of these things here and Winnipeg and over the last three years and very proud to say from 2017, 2019, you can see that are chronic lung disease rates under 29 weeks have been falling in the blue bars where, as the rest of handed a have been going up. So I think that we have demonstrated that when you, uh you know, as as as Steve Jobs says, when you know what's going on, when you do that auditing and when you identify where the issues are, you're halfway there. The other half is then putting into practice what is best practice. So in conclusion, I would like to say pulling of results or pool it's very pooling of results of small units allows comparisons that can lead to targeted improvement. Normal best practices. A Rexhep did ast part of the epic. But I would encourage people to say, If you're not going to adopt something critically, ask yourself, What is it that's keeping you from adopting it? Is it personal preference, or do you have the data to back it up? Thirdly, data drives, results and continuous quality improvement can alert to trends and allow for adaptation Really time. And I thank you for your attention today. Thank you.