Transcript Video It Works in Neonates < Back to Summit23 Cracks in the Ice It Works in Neonates Presented by Professor Daniele De Luca And uh our first speaker will be uh on virtual Professor Danie de Luca. It's my pleasure to introduce him as medical Director of the division Pediatrics in another critical care in the Belaire Hospital in Paris. And he is the current president of the European Society of Pediatric and Mental Intensive Care. So I think no better than him. We could have this lecture on whether temperature management works in neonics. Daniele. Are you with us? I can see you. So the floor is yours and because you are of course virtual, we will take the questions for you at the end of your lecture. Thank you. Thank you. Thank you very much kind introduction and thank you for inviting me here. I'm very sorry to be only virtually present, but I hope you will be truthful. And I'm also very uh open to collaboration in a multidisciplinary way, which is something that I uh that I truly care for uh meaning collaboration between the neonatal pediatric and adult IC U. So as you know, uh hypothermia works in neonate, so I'll try to show you a little bit of the history, this uh therapeutic intervention in neon A I DS and the part of physiology behind in order to understand why eventually it should be working in neon A s uh compared to why it's more or less working in, in adults. And, um, by the end of the presentation, I also give you some thoughts about nomia because as you said, um, it's not about, it's not only about hypothermia, it's about, let's say temperature control or temperature management in general. So, first of all, um uh the hypothermia has been a sort of a unique example in United Critical Care. Uh It's probably the only one in the last year when we have been so strict and we have been so good because we started from the animal studies. So we understood a little bit better, the pathophysiology, we tried the intervention some case, the and then some short term uh small physiological studies in order to understand what eteria was going to change and then large trials to verify efficacy and eventually safety, that's the right pathway that should be always forward. But we are not so used to do that anymore. And at the end, uh even the uh most important societies here, you see the uh the paper from the American Academy of Pediatrics, but because it's historical, but I can show you many others from Europe and from international societies, um let's say, uh embraced the evidence and made strong recommendations for the use of hypothermia to treat neonatal encephalopathy. Basically, when I speak about uh big large randomized control trials for this intervention. I'm referring to the ones that you see here, the N IC HD trial, the Cool the Cool Cap trial. And uh and then eventually the toy trial uh all demonstrated the, the same thing in terms of benefits will go over that. But also very interesting we based on populations that were selected with really very, very similar criteria. This has been facilitated significantly um the uh creation of evidence, eventually the reduction of meta analysis. And so the fact that evidence was perceived as very much solid by all the stakeholders. And I know that at least in our field. But I guess also in D IC U is not always like that. Sometimes it's very difficult to aggregate data because the uh uh trial inclusion criteria are very um different or, or, or or variable anyway. And so at the end of the day, the result is that the evidence that we can eventually provide is not so solid. So here you see one of the F me analysis and uh you see uh death or major disability in survivals with neonatal perinatal encephalopathy, you see the diamond is on the left Fabri um apo hermia. And when you um divide this outcome into the different uh major disabilities, I would say that it is always the same uh for uh cerebral palsy blindness and so on and all these disabilities. And then again, um um uh for moderate to severe hypotheses, encephalopathy, you always have the same although with a little bit different uh odds ratio, but diamond is always on the left side. And so you see data are very much consistent, even if you analyze them from different angles, number needed to treat is eventually similar. And I would say very low for those of you that are not very well versed in statistics. That means that we need to treat six or seven babies with hypothermia to prevent one death or um uh one severe neurological uh disability. And just to give you an idea, um the use of a CPAP as initial resuscitation in in pre them babies in order to avoid Cron lung diseases and number to treat the 25. So it is much larger. And so that means that the uh f of the intervention is much lower compared to hypothermia, although we're talking about about the different disease in, in different patients. Now, another important thing you have to understand is that the pathophysiology of uh neonatal encephalopathy due to a perinatal ischemic uh insult is extremely complex. It looks extremely different from, let's say traumatic brain injury or from um encephalopathy due to vascular accidents or other type of injury that are more common in the adult critical care. So here you see there is some genetic and epigenetics, some maternal factors for sure. There's a placental pathology at the heart of the problem mainly causing epoxy and ischemia to the fetus and neuron. A although that may happen well before the delivery, close to the delivery during the delivery. And sometimes even after, if um something has been already started before, in some cases, there are metabolic disorders, a peral infection. Some other cases, there are also, but it's extremely rare. Um uh some uh uh vasculopathy and so some vascular accident. But in these cases, obviously, um apo has not indicated what we are actually talking about is an epoxy ischemic in salt, that is at the heart of the problem. And is the uh cause for, I would say more than 95% of um neonatal encephalopathy uh due to paray. So, again, that's extremely different from TB I or for primary cardiac arrest and speaking about primary cardiac arrest. I'm sorry, here, the table is not very well visible, but that's just a paper that we published a few years ago in resuscitation when we used um um hypothermia for the post cardiac arrest in a series of neona that the cardiac arrest not right at the delivery within the perinatal asphyxia, but a few days later for different reasons. But again, even in these cases, the cardiac arrest in unit is always related to epoxy as an epoxy origin. Uh It is extremely rare to have a cardiac arrest due to malignant arrhythmias or um you know, um uh ischemic cardiomyopathy. These type of things are very, very rare um uh in neonates uh unless you're treating a baby with congenital artifacts. And we saw at least from this uncontrolled case series that even in these cases, um just because the pathophysiology is the same APO was extremely effective and helpful to resuscitated babies. Now, going more into the details of pathophysiology of epoxy is chemical encephalopathy or brain injury to prenatal asphyxia. We have the insult that as I said can be very far during the pregnancy before the birth can be close to delivery or even in the middle of the delivery or later, there's a primary energy failure that is very short, I mean causing image and necrotic cell death. And then there is a short uh cerebral metabolism recovered that can eventually go into a second phase with a lot of energetic demand that can aggravate the insult and this is happening after six hours for several days after the insult uh leading to apoptotic cell death. And this is what we're trying to prevent with hypothermia. We can do almost anything about the first phase. But the second phase is something that we can prevent uh because we can lower down the energetic demand, metabolic demand, the mitochondrial dysfunction and eventually the caspase activation. Those are the enzyme recreated in the second phase. There are even some caspase individual that are still experimental. But for sure the uh abu can lower the enzymatic activity in general. And so as well, including uh the the activity of caspase. So this pathophysiology is reflected in the criteria used internationally to start rule by the epo hermia um uh on the first day of life. And uh you see here, there is a combination of clinical criteria like the apgar score, the need for violation. Um ph uh basic sets or lactate is one or the other of these and this is the bunch of the criteria, but it's not enough because then on top of that, the babies must have either a clinically evident encephalopathy. There is a particular uh clinical score used to evaluate that the so called Sarna classification or they must have electrical science of encephalopathy. Um We usually with an amplitude integrated eeg because it's what we use in the NICU unless um um you are in a uh let's say um lucky situation where you can have a full eeg interpreted very closely by very quickly by a pediatric neurologist, which is pretty, pretty rare. There are two types of hypothermia that have been used. Um in Nunes, there's the uh um uh Boba Apo uh and the uh let's say selective apo only dedicated to the hand. Um There's no clear comparison and no strong data, but now we tend to prefer the V body epo. Here, you see the difference at the end of the EPO between one baby that is treated in terms of MRI uh with the full body cooling and the other one that was treated with just a selective head hypothermia. The um core of brain injury at the MRI was significantly better for the full body teria. Although again, we don't have a large trial. But now for this and for practical reasons that I showed you before where they show you in a minute, uh we'll show you in a minute. Uh the whole body dermic, what is being used worldwide in 99% of cases. Um Although again, if you look at the trials in terms of uh large studies and big outcomes here, you see um uh selective head cooling, 0 78 of odds ratio for the reduction of mortality and 0 75 when you use the full body cooling. But as a matter of fact, the problem is that it's more I would say practical and generally cost effective to use the full body hypothermia. Why? Because um the severe perinatal asphyxia is not only associated with the um brain injury, but it most of them, particularly in severe cases associated with multi organ uh um failure syndrome. And in fact, because of the centralization of the circulation that is happening when there is an insult before or or or during the delivery, there are other organs that are suffering. We have almost invariably um uh myocardial dysfunction with very high troponin, uh relatively severe or very severe acute kidney injury. We have problems in terms of bone marrow and a lot of um needs for transfusion and plasma replacement and coagulation factor replacement. And so, obviously, the um um uh boba eteria would be able to lower inflammation, the metabolic demand. Also, these other organs uh is theoretically able to provide a more constant and uniform cooling and an internal cooling, which is what is actually more important. And uh sometimes the parental asphyxia is also associated to neonatal A R DS due to macon aspiration, which is a particular form of primary A R DS, which has been demonstrated. I'll show you some data to be responsive uh to uh hypothermia. Um And by the way, there are also, as you probably know, I mean, those of you that are working in the isu there are some case the and small uh control studies demonstrated here and then that primary A R DS can be, can have some benefit in being treated with, with a term that has been particularly uh tried during the COVID era. Uh uh Obviously. So here you see a little bit of our studies regarding the uh effect of hypoderma, whole body hypoderma for perinatal asphyxia, brain injury um on the lung because about in these babies, the the full body epidemic was started because they respected all the criteria that I showed you for brain protection. But we could study eventually what was happening in the lung as well. And here you see those were babies without lung disease only all the criteria for feed for brain protection to, to be trial criteria basically. And you see here, the decrement in terms of pro inflammatory cytokines in the um in the bal uh in the lung. And then again, also the decrement in phosphor aba a activity which is the first enzyme of the inflammatory cascade and is also able to i surfactant Follis that is uh very much being reduced by hypothermia. If you compare before the uh the onset of U by the hypothermia and after 72 hours uh of the treatment, as I said, perinatal asphyxia is inducing um uh neonatal hypothesis, chemical copy. But it always or very often associated to meconium associated A R DS. Why? So, because during the centralization of the circulation, there is, as I said, an optic ischemic cell, even in the, in the heart and in the gut, the gut ischemia is creating is pushing the passage of the meconium. So the first tools of the neonate yet in the mother's womb in the amniotic fluid, which is a very bad time. And it's something we we shouldn't see usually. And obviously, the meconium is full of phospholipase, the pancreatic phospholipase and other toxic agents. And one is entering into the amniotic fluid and then in the lung can create a very severe A R DS. So here you see what happened to babies with Meconium Mas Creation syndrome, treated in hypothermia or normothermia depending if they add or not. Uh if they fulfilled or not. The criteria for uh starting hypothermia for brain uh protection. And you see here that those babies that were treating under um hypothermia at an oxygenation index better, significantly better than those treated in normothermia. At the end of the treatment, this was a little bit similar. But that because in that particular study, hopefully the mortality was very low. But what is more important hypothermia significantly reduced the duration of invasive ation respiratory support as a total and also IC U and hospital stay. So all in all this is why the guidelines internationally. And again, I'm only, I'm only sharing with you the American ones. But it's just an example says that all medical center of a third level should offer hypothermia. Um uh with this criteria that I just showed you and there should be a dedicated training program for those centers that are just first or second level center that they should never do hypothermia because it's something very complex. But there should be um a training to recognize the babies at risk to um to need hypothermia and to transfer them without any active warming at a minimum uh uh as quick as possible to the third level center. So to a nicu to a unit intensive care unit in order to start hypothermia within the first six hours of lives. Now, we even have some data very recently that, that demonstrated that if you arrive a little bit late, sometimes it may happen depending on the medical geography because the NICU is pretty far away from, you know, the, the, the centers and you get the baby and the baby is retrieved only, you know, after six hours, but yet before 12 hours of life, well, it would be better anyway to start up with. You can have an efficacy. You can have an advantage anyway. But surely there is a logistical problem and it's very much important to coordinate the transfer of these critically ill babies. And in some areas, it's still a little bit difficult. So here you see some uh some ice cubes. Why? Because that's probably the um I would say the low, the lowest technology possible um uh to provide APO and it's funny to see that in Africa when obviously they don't have all the monies and all the machines that we use for EPO, they did try this. And you see there are three or four trials that actually demonstrated that at the end of the day, even if use such a very simple technology, um you have a reduction in mortality um uh uh in the nicu or uh mortality of two years of age and even in neurological morbidity, the the diamond is always on the left. So it's really, really important for us to do that even with the this low technology. Otherwise you may ask yourself if you OK, we, we, we do the cooling with the mattresses, with the patches with, you know, different devices even with the ice cubes. But what about lowering the temperature of the air that is going through the ventilator? Um, and the humidifier, uh and then into the baby's airways because obviously all these babies are or should be intubated and mechanically ventilated. Well, we tried this because we were curious to see if actually lowering the temperature of the mix of the gas mixture, um uh was changing something, but actually it's actually the same. So there is nothing changing if you lower down temperature of the uh gas mixture to 33.5 degrees, which is the uh temperature that is used um during apo, by the way, and we publish these results in resuscitation a couple of years ago and nothing is changing in terms of vital parameters and not even um not even lung function and lab mechanics. As you see here, compliance resistances are always the same in these babies. Now, this is our situation. We're located here. Um And uh we're responsible for all these area which accounts for more or less 18,000, 20,000 deliveries and we do more than 70. Actually, this has been increased uh lately um uh hypothermia per year and um which makes us the referral center for all the um uh small hospitals all around and we go retreat actually, these babies. And sometimes here is the picture that I really wanted to show you sometimes in order to start hypothermia within the first six hours when we are absolutely sure that anyway, the criteria already met. Well, we start the hypothermia when we go to retrieve the baby. And then we uh provide that uh during the transfer you see here in the uh in the mobile nicu. Obviously, this is not always the case. Sometimes this is possible just for n admission because we have time, which also um is also helpful to provide, uh let's say deeper evaluation of babies, you know, through the A eeg, then we go in the ICU and, and et cetera, but you must also be prepared to do that during the transportation. Uh If you really want to uh uh let's say, avoid losing any baby that should need this type of uh therapy. And besides, as I said, it's not only about teria, these devices can also be used for normal theia. Now, no derm has meant in um uh neonate for a long time avoiding hypothermia, pre babies. Just because hypothermia, pre babies is extremely dangerous for the brain, for the heart, for the lung, for appearance, for most everything. But this is something that has been uh let's say, provided quite easily with the incubators, right, more than incubators are able to provide a good temperature control. And also the humidity control, which is extremely important for uh uh pre babies. Extremely pret babies having um a very immature skin and so through the skin, they can lose uh electrolytes and water and so on. But now, uh let's say taking advantage of the adult um experience, we also have uh let's say nomia to be provided in the particular situation where we know, for example, that fever would be detrimental or could be a problem. That's a case that I wanna show. It's um a se shock was eventually a relatively uh relatively pre baby that because of septic shock developed in the er DS, mostly organ um a failure and um food overload that this is why it was on CBBH was a small baby for CBBH. But we have now the capability to do that with a particular secret as it is here. And the baby was on the mattress just to avoid hyperthermia just to avoid uh fever. And that's something that can be very, very much important in this um uh very fragile patients. Although obviously, um uh centers need a particular training to that. And uh the NICU should be well equipped and trained as it was a sort of a more um let's say, uh uh mixed uh unit somehow it's just an example. Um uh but the something that I think it can um eventually open up the mind and uh uh stimulate a little bit of discussion because I'm very much sure that these machines, they may have other indications behind uh the uh just the treatment of brain injury due to prenatal asphyxia due to epoxy ischemic encephalopathy in the perinatal period. Um that's the setting. And I know that is a brain like uh uh sort of a small space lab. But this is actually what is happening in our NICU when we receive a baby with petal affection. So, um ischemic um epoxy encephalopathy because it's not only about the temperature, it's much more about the mindset and the capability to uh measure as much as possible. The more vital parameter you measure, the more will be tailored your intervention and clinical management and the more will be um uh easy to save these babies. Now, I don't want to lie to you. Some of these babies are extremely uh not so sick. Those are the babies with mild uh perinatal asphyxia, use encephalopathy and there are some of them that are also being uh let's say treated in, let's say lower level centers without all these equipments and all the expertise that's fine. But when it comes to moderate and even more severe perinatal asphyxia, that is also coming with all the other complications like A R DS kidney injury, uh myocardial dysfunction and so on. You can't avoid having all this. You can't avoid give a lot of transfusion eventually going in a circle portal dial and sometimes even emo and as you can imagine, this is something that requires a lot of um uh let's say expertise and techniques and a setting like that when you recognize the cooling machine. But you also recognize the exo circulation, the ventilator, eventually in nonconventional ation, the needs the um full monitoring and so on. So, um thank you for your attention and I'm sorry again to be uh there only virtually and I'm happy to take all your questions. Thanks a lot, Daniele for the very nice api lecture. I will open this for uh questions from the audience. Are there any questions? Are there any questions? Are there any questions? Of course, if there are no questions, I will start with the questions that oh, the physician want you to respond, how to explain in your opinion? The difference of striking evidence in fever apo for neonates. When compared to the controversy we have in adults, you've made the point. It's a very rapid uh management. It's just a delivery patients at the hospital, very rapid cooling because its small size. Do you select patients based on a a not like everyone will go into it, which are your viewpoint? How can we integrate what you presented for the controversy we have in adults? Yeah, there are several points that are responsible for that in my mind. And I'm happy to share that with you because um I learned a lot from adult trials in other fields, particularly in respiratory critical care because in respiratory critical care in the, we did exactly the same mistakes and we need to learn from you. Uh In this case, probably we can't teach you something. And for me, the the First of all, our brain injury is extremely homogeneous. It is something that is due to this to ischemic and uh hypoxic insult. Um most of most of the time. So we exclude the ABC the vascular accidents and so on. I know that for adults is very much different. So it's a problem of case mixed selection. Second point, the onset of the injury in babies is relatively fixed. As I said, it can even for the birth. But besides the 16 cases, we know that it's related to perinatal asphyxia, as I said, so it's perinatal located somehow when it comes to an adult and the medical emergency team is going down to a three in most of the time, you actually don't know what happened and when it started to happen and you relay the information from lay people and you actually don't know that. So again, case mix, you probably should select better the population. And I'm sure that when you have a primary apo can insult, there's no reason uh for the technique not working it out. We do not have a different physiology compared to a newborn. Um Yeah, the the third point is that maybe we quicker, we try to be quicker. I actually do not know the data regarding the delay of treatment uh in adults, but we are indeed quicker and uh and that can be helpful, that can be helpful as well. Thanks a lot. Uh Do we have another question, maybe another quick question before leaving. I maybe have a second question for you. Then we will have tomorrow a lecture on the future of TTM studies in adult patients which are the remaining questions to you that are necessary to be studied randomized trials for neonates concerning the use of APO as it duration? Is it methods? Is it a rearming rate or you have most of the responses to? There are open, we are talking about there are several open points. First of all, usually, uh I mean, we we have the right to cool down babies provided that uh they have a gestational age equal or above 36 weeks. So a term or one week to the term. Nevertheless, we also call babies after five weeks but there are just uh some case the here and then there is no evidence for the others and that we know that the more you lower, the a the more you pay some risk of hypothermia brain injury. So we need to understand better when we need to place the treas second point, the duration is 72 hours is very well. Um let's say understood, we do not know conversely if uh the temperature can have an effect, it seems that very deep hypothermia like 32 degrees is detrimental, but we're calling at 33.5. But there are reports that are saying that maybe 34 maybe 33 can be equally effective. That's another good point. Third point that is the closest to my heart, as I showed you, there is a beneficial effect in uh for example, neonatal A R DS, which is al almost always a primary direct A R DS in these particular babies because of meal creation syndrome. But we only have relatively low evidence data despite the solid part of physiological and translational data behind that. So we need a trial for that. We need a trial for hypothermia as a treatment of unit A R DS. And um and that's the uh the, the, let's say the, the, the main bunch of questions for neonates. And then there is a second one which is somehow related to the epiderm. And it's about the so called neuro protectors. There is a number of molecules that has been tried together with epiderm. Uh in order to enhance its effect, we've been, you know, witness it like um epo erythropoietin, Senon, even as gas um melatonin uh who knows how many others? Still, there is no clear effect. Still there is no clear evidence. Uh but this must be subjected to more um higher quality and larger trials in order to be understood if that they do have, they do have an effect or not. Dra Thanks a lot for your participation. Thank you. Created by
