Transcript Video What is Different, What is Common < Back to Summit23 Brain Injury Management What is Different, What is Common Presented by Professor Chiara Robba, Professor Daniele De Luca & Dr. Thomas Pellis Moderation by Associate Prof. Katia Donadello Good morning, everybody and welcome to this second day of the Temperature Control 2023 summit. So I have the pleasure to introduce this first session of the morning before the topic session that will be presented thereafter. So I have the pre pre the pleasure to moderate this session and I will invite here now the three speakers of this debate of this discussion. So ladies first uh professor is Professor Kiara de Rob, Kra Robba. So she is associate professor in anesthesia and intensive care at the University of Genova. Please have a seat while I'll describe you. Uh She uh works at the San Martino Hospital in Genoa and she, she is associate editor of uh Intensive Care Medicine and the chair of the uh neuro Intensive Care uh section uh of the European Society of Intensive Care. Then I'll introduce Daniele de Luca. Uh he might be connected, might be connected here. He is, hello, Daniele Daniele. After a graduation in Italy, he moved to France and he works at present at the Medical Hospital Bela in Paris. And he is the current president of the European Society of Pediatrics and neonatal intensive care. Last but not least. And as you can see it is an Italian rope. So, uh we have uh Thomas Pis. Um he has been introduced yesterday. He works in Noor de No. So, uh Friul Cidal, something like this. Um, after being abroad for many years, uh both in the US and in North Africa, uh and in south of Italy for a part of his time. So, um, as you might have read, this will be a discussion without slides. So I might ask a question to the speakers and uh we'll try to um communicate all together. Please remember that you might ask your own questions anonymously. So, no fear, no stress using the app that has been, has been introduced. And during the talk, I'll be able to read your questions and to pose them to the speakers. So we might be able to have a throughout debate. So, first of all, uh as you might know, these three speakers are fundamentally devoted to three different items. So Daniele is mostly devoted to small human beings, uh Kiara to neurologically injured patients. And Thomas is mostly devoted to cardiac arrest patients being involved in the TT M trial previously. So, uh my first question to the three of you uh might be what, what would you uh aim to um get to when you decide to um apply temperature control to your patients. Kiara first. Thank you, Katia and good morning to everybody. Um So what I aim, I think uh this might be one of the only questions where we might agree. So what we want is to avoid the secondary brain damage uh in brain injured patients when you have a patient who arrives in uh in your IC U, and you look at the CT, there is also always what we call the primary damage where you have a hemorrhage where you have already ischemic areas. And this is, these are lost neuronal population. There isn't anything that we can do about that, but there is very much that we can do about the other areas of the brain, what we call the secondary brain damage. And as we know that the temperature is an important factor to minimize and optimize secondary brain damage. This is our first goal and aim perfect Thomas. Thank you Katia and good morning to everybody. Uh Thanks for the kind invitation to this wonderful um conference. So my, my point is uh again, as, as as Kiara said, it's obviously a secondary brain injury, but uh it is also a A mm um It's the main focus is the fact that our patients die mainly due to uh brain related damage. So our main goal, once we have resuscitated the patients, when we, once we have cleared the cause of cardiac arrest is to preserve a neurological outcome or to try to improve the chances of uh a good neurological outcome. Our main focus is that the fact that after the first two days, then death is mainly related to neurological injury. So that's our main goal and we have to strive to find a way to do it in a uh homogeneous way throughout uh the whole group of doctors and nurses that take care of the patient. Doesn't have to be uh every time that we invent the wheel or hot water, it has to be something that is highly reproducible And for the rest of the people that are looking at us and how we do it, it has to be a clear message that although the evidence is very conflicting coming from trials, me analysis and all that we heard yesterday there is still hope and it's still a very intriguing subject that of hypothermia and probably uh um the next uh Panelist is gonna work on that uh ex extend on that topic. Uh And so we, we, we haven't given up hope that modulating or controlling temperature, we can achieve really something uh important for our patients. Thank you, Daniele. Do you have something to add or to modify compared to what has been said? Um No, I'm not gonna modify anything. I uh would just say that above, we aim at the same purpose to the reduction of avoidance of the uh secondary brain injury since the primary one is something we cannot touch. And we, um as a matter of fact, we are however, in the uh perfect situation, uh because as I said, yes, the the variability of the timing of onset of brain injury neonates is relatively limited. So we know time window when we can act and we have a different part of physiology, pretty much homogeneous. And um and this is probably why or one of the reasons why there's such a strong evidence in UN A. So with this in mind, what happened is that in the critical care, um the, the evidence is so strong and even some conditions that have been originally proposed are suggested as a contraindication for w by the hypothermia for epoxy chemic encephalopathy. Uh There are no more there. I mean, we were force in any way to do hypothermia, which is supposed to be really the uh the primary uh emergency, the primary decision to be taken, even for medical legal reasons. And this means that eventually you must uh work it out with all the rest. You have to uh uh you know, manage hemodynamics, you have to manage bleeding. Uh and, and all these things because none of them is a good reason not to start or to stop w body apim in, in this neon and daniele. If my, I might ask, when do you start temperature control in your uh young uh patients? As I said yesterday, during my presentation, I'm starting, I'm starting, I mean, all the international guidelines required to start uh before the sixth hour of life. Although there are some reports showing some benefits even if you are a little bit late. But anyway, before the 12th, before the 12th hours, thank you. And Thomas, uh, why is in your opinion, uh, um, why is there such a strong, uh, difference between the evidence in neonates and the evidence, uh, in human trials and human results? If I knew the answer, I wouldn't be here. I will be writing it in a paper. But, um, we, we, we haven't yet figured that out. And uh we heard yesterday that uh many believe that it could be in the timing um with which we start uh modulating temperature, taking control of temperature. And in this case, if we wanna look at the um intriguing hypothesis that it is taking the temperature down to something like we do in neonate. So 33 °C, we might probably have to start earlier. And there is an a, a trial that is gonna be run shortly in which uh we basically will reproduce uh what has been done in the princess uh trial with the add on of all the experience that you have, we have uh gained in this uh in these years. Um This might be one of the reasons another reason could be that the brain of an adult or an aged adult is different from the brain of a child. And so there is no more that window of opportunity. And finally, I would uh I would be interested in knowing if it is really fever that matters or not because in, uh, in all our uh experienced, uh it, you know, our, our, our uh spectrum of uh brain injury uh causes. We, we, we, we really don't know yet if fever is just associated with worse outcome or it's a cause. So if there is a causality that leads to worse outcome and Daniela, if I might ask, uh being aware of uh uh the great results in neonates and small human beings, what might you suggest or might you um give as an advice uh in order to try to change the results in adults? I mean, do you think, as I said, as I said yesterday and this is a concept I really believe in not only for derm but also for other situations. I think that uh there is a bunch of different factors here. One can be about the timing as my colleague already said, which is also, you know, the, the the time needed to lower down the temperature in an adult. And anyway, the time of onset, but there is another one very important and is the um the case mix the different part of physiology. And I tend to say that at the end of the day, the differences are related to a mix of these factors because again, we have a primarily uh original hypos chemic in salt. It's not always the same for all adult patients. So um beside the timing and let's say the speed to achieve the targeted temperature, we you should also probably try to select some uh subpopulation of patients that can actually somehow mimic the the newborn patients and have benefits from hypothermia. Because I don't believe that hypothermia like any other therapy is the metric ballet for every type of brain injury or for every type of um disorder. So if I might rephrase what you both just said, we might state that the setting and the pathway that the patient experience might change, the result of the action that we might be applying. Isn't it the both of you? I mean, if you, if you just say that uh uh the the neonates or the, the pediatric situation is different because of the p the neonate that you think I know that from the adult critical care physician that may seem similar. But in fact, it's not, it's very much different. Hypothermia works in neonates with perinatal brain injury just because of all the reasons that we uh we mentioned it, we are far from birds. Uh the part of physiology of brain injury can be a little bit different and can be approaching what is happening in adults. And besides that, we do not have strong evidence in kids at all. We only have a very strong evidence in neonates in the first hours of life. Thank you. And uh Kiara, uh why do you think that big trials in adults have difficulties to show differences or impacts in patients outcome. OK. This is a $1 million question. So, thank you. I will try to summarize it in uh the best way I can. So uh we have to think at least for neuro critical care that there are two main issues. One is the temperature itself and one is the effect of temperature on the intracranial pressure, temperature itself increases the cerebral metabolism and this causes a sort of stress for the brain. So, hyperthermia must be always treated. And what we do is to treat it as soon as possible. When you ask them, what is your approach? I think that we have to be aggressive in treating hyperthermia as soon as possible because the risk of secondary brain damage is higher in the early phases where the brain physiology is more unstable where when the patient is more unstable, when you have to deal also with systemic complications, et cetera. But then there is also the problem of intracranial pressure, which is itself a huge cause of secondary brain damage. And in neuro critical care, there are, there have been a lot of trials trying to understand whether hypothermia can reduce IC P and therefore can eventually improve the outcome. Many of these trials have failed, many of them are negative. Many of them have suggested that hypothermia is also detrimental. It's difficult to tell you why. But my opinion is always about the algorithm and the structure of the methodology of these trials. I give you some examples if you compare two groups of patients where they arrive in the IC U and they have increased the AC P and you randomize them to receive manito or anti Demien drugs against cooling them down to 33 degrees. Well, I'm not surprised that the patients who were cool at the worst outcome IC P is reduced because hypothermia reduces IC P. But there is a price to pay which are the side effect of hypothermia. And maybe if you use hypothermia too early, you only see in the results of the big trials, the effect of the side effect, maybe many of the patients who were randomized in this arm, they just needed one vol of hypertonic saline and man. So this came to the idea in neuro critical care that hypothermia reduces IC P. This is for sure we know it, but it has to be used in the right time. So it has to be used as tier three treatment. We have a staircase approach for the treatment of intracranial pressure. And hypothermia is at the latest part of this staircase approach. It is in the guidelines considered together with the compressive ectomy. So as a very aggressive treatment, first, we have to try what is less harmful and then we have to try uh all the strategies which can eventually rescue our patients. If we use it in this way, it can improve patients outcome. So just to link to what you were saying, uh I have some questions that arrived and one is uh a one. So which temperature do you want to achieve in TB? What is uh for you nor hermia? How do you treat shivering? What medication do you give to prevent, to treat proxy, small sympathetic hyperactivity, right? These are many questions. So let's start from the first one. So um temperature compared to the general population, we have to be more aggressive. Recently, there was a very nice editorial on intensive care medicine which was called Less is more in terms of fever, which was about the fact that in the general population, there is a sort of feeling that it's not just about treating the fever itself, you have to consider whether the patient has organ dysfunction or not. So you have to be less aggressive. This concept cannot be applied in neuro critical care patients. So in the recent guidelines that have been passed, published on cerebrovascular disease and we are ongoing to finalize the guidelines on TB patients and temperature control in TB patients. We recommend that always if you have a 35.37 0.5 degrees, this should be the trigger to start your your treatment in all these patients, especially in the early phases. When the patient is at higher risk of secondary brain damage. This if you have a normal IC P, then if you have an increased I CPA refractory, increased IC P, you cool down the patients. But the guidelines suggest to go to a target of 35 to 36 degrees. This is the result of a number of physiological and clinical studies which have demonstrated that if you look at the effect, you have to imagine a graph with temperature, systemic temperature and IC P. And this graph says that you have an important reduction in uh is in intracranial pressure when you reduce the temperature until 35 degrees. And then at some point, there is a sort of plateau. So the effect is reduced on the reduction of IC P below 35. Uh The other point is the cerebral oxygenation because we have always to think about the cerebral metabolism. Physiological studies have taught us that fever is detrimental only if you have on the metabolism. But if you have good cerebral oxygenation, this can be sort of rearranged or um managed. I mean that the biochemistry of the brain is not so importantly impaired. So it depends on the substrate. But if you reduce the temperature below 35 you will also see a reduction in the cerebral oxygenation. Despite the systemic oxygenation can also increase because P BT 02 is the result of delivery and consumption. So the oxygen arrives at the level of the vessels. But you have a shift in the dissociation curve of the hemoglobin. And you have a reduction of the metabolism. So the brain doesn't use it. So, because of these studies, the idea is that 35 is more than enough for this. OK. Thomas, how do you treat shivering? Actually. Uh I heard yesterday that there are uh there, there was some interest on shivering. So I added a couple of slides to my presentation but uh we treat shivering. Mm Can I first of all comment what uh Bruno uh what uh Daniele was saying? Of course, uh I wanted to, to give an idea to the audience that why uh temperature management or temperature control in, in adults is so intriguing. Still, even if uh the TT M one and then the TT M two gave the false impression that there is no need to control, to control temperature. And that's because you, you have seen that in, in neonates as the NSA, it's very standardized and, and very well defined population as in animals, we are able to standardize very well what we do. And so we, we are able to induce hypothermia in very well standardized animal models. And in these two set in, in these two population, it works brilliantly. It's, it's, it's very hard to, to miss AAA good result. They keep doing studies and they all show up positive. So it's, it's, it's absolutely intriguing because this is also a probably the only translational model in uh in, in, in neuro resuscitation that we have from animals to humans. I don't think there are other areas in which this connection is so clear. Now, if you go then to Children and we have very lousy studies in Children, very homogeneous. So we cannot really give a message on that yet. And then you go to, to adults, you keep linking these dots and when you get to adults, the dot sort of fades. No. And again, as, as Daniela was saying, our population is not standardized, the age varies, the comorbidities are important. So we are really in, in, in, in, in a hard time uh in, in giving a clear, clear message, but it is uh it is hard to forget what happens before the other two dots. So we it's an, it's as a, as a as ciara was saying, it's a sort of engineering problem defining the way you have to do it. And why are we still insisting on treating everybody? That's another good question. Why are we still finding looking for a magic bullet or a suit that dresses up fits for everybody? And that's because as you heard yesterday, we don't wanna leave anybody behind. We wanna so hypothermia die or temperature control done at 36 and at 33. And I'm spoiling probably my presentation later on. It's actually not that harmful, but we don't, we don't see a real problem with it. Actually, it has a benefit. It, it pulls along a huge investment in uh attention and assisting a patient is probably the most effective drug we have taking care of our patients is probably the most effective intervention we uh we have and that's why these patients in retrospective analysis go better because they have a plan, they have attention, they have studies, they have a, a path which is standardized because we rely on a standardized approach. We, we know what we're gonna do tomorrow and the day after tomorrow, we're gonna standardize their protocols, their neurological, their prognostication, which is again, our hard end point because remember, we are targeting the 70% mortality of these patients, which is related to uh neurological dysfunction. So uh what was your question? Uh First of all, I would like to, to know if Daniela has something to ask. Yeah, I cannot agree more. You um actually said it all. And if I can be the link between the two of you guys, that's exactly the point. And um at the end of the day, from the trial, methodology's perspective is just the difference between doing a pragmatic project and put everybody in it just because it's easier to recruit is more, easier to understand because you wanna save everybody as you said, or doing a more explanatory trial trying to targeting um in a more um let's say accurate way, a particular population that is representing a particular part of physiology with some comorbidities and not all the other. So having something that is more standardized and close to an animal experiment and I totally agree with you that this is exactly why, why it is working together with the timing, which is eventually another confounder in neon A. Now, if I can give a suggestion, I strongly believe that one trial can kill a good drug or a good technique. So while it's very much easier to do, you know, pragmatic trials and uh without all this, um let's say sub CGO organization, we you should be very, very careful because then at the end, the message is that hypothermia is not useful for anybody and it's not working anyway and so on. And we may eventually miss a positive effect. Certainly not for everybody just for a subpopulation. But maybe in depth subpopulation can be extremely useful. Thank you. So, the, the question was about shivering and about uh paroxysmal sympathetic hyperactivity. That's not for me. Uh So this is a very important point because uh uh paroxy sympathetic activity is a huge problem. Uh it's associated with the worst uh outcome. And uh uh basically the path ofsi is quite complex and probably we haven't understood it completely. But what we know is that it is related to a lack of uh uh of discussion between the higher areas of the brain and the lower areas of the brain which cause this acute hyperactivity with hypertension, tachycardia fever, et cetera. And it's related to a paroxysmal activity of sympathetic and parasympathetic system. So, because of this pathophysiology, the first uh drug, the first type of drugs that we use are those which have effect on the beta and alpha receptors. So we generally start with the beta blockers or alpha agonists. Like for example, the cloNIDine works very well. We should also keep in mind very often that these patients have severe Audina, which means that the trigger for parasympathetic activity can be any type of uh uh of sensation or feeling. Even when the nurses wash the patients, this can cause huge pain and can trigger the the parasympathetic activity. And this is why we use opioids. Uh We use neuropathic drugs. We use drugs which act on uh on the gaba receptors in order to reduce the uh the the the cause of the parasympathetic activity. And this is, is not enough. Unfortunately, we have to start the sort of sedation. Often we use also the propofol for refractory cases as you know, we not just in your intensive care, but I think in all the group of patients, we have understood that we don't have to keep sedated the patients because it's not the sedation that protect the brain itself. It's, it's much more about this when I started in I the concept was keep all the patients sedated and hypothermic and keep them still. We know that now this is wrong. But if you look at the indication for sedation in neuro critical care are basically refractory intracranial hypertension where you cannot of course, wake up the patients, uh status, epilepticus and paroxysmal activity. So, unfortunately, we arrived to sedate these patients. OK, for the three of you, which is the, which are the first drugs or the typical drugs that you use to treat shivering. Because I might believe that the question has been posed several times. So it is really something that is uh uh of interest without spoiling your president. So I see Danielle is frozen or then I'm here. Can you hear me? Yes. Well, I must admit that um, we don't have so many data regarding that in, in neonates and not even in Children to be honest. So we mostly copy what we know from you guys. And, um, besides, I would say the shivering, I cannot remember when I see that in, in, in, in neonates under rule by the APO. It's something very rare. I may have seen it a couple of times but not so commonly and would be interesting to understand why. But again, um, the few times it happened, we, uh, did the only thing we did and it's probably stupid but has been sedated more deeply to patient and paralyzed him or her period. There is no consensus and there are no strong data, neither regarding sedation in neonates. Um I heard Kiara um regarding that, um, there are some animal data in um, new animals demonstrating in any way that when you cool down these animals with parental fix with the positive c encephalopathy, sedating them is beneficial in terms of brain injury. But again, it's a very, it's just a rough data. It is the beginning of the history from the other way around. It's also true that on average in an IC U, we use far less sedatives and uh and this type of drugs compared to an adult IC U particularly recent years since we know that any way they can have some negative impact on the neurodevelopment later. And we have to remind that our patients are rob subjected to a development later if they survive still, uh we sedate them not so deeply. I would say during apo drugs we use are the common ones. I mean, you can use Remiel or morphine and, and eventually associated with Midazolam right after the beginning of the uh amplitude integrated eeg because you want to have a verin period in order to evaluate if you go on the R or not. Um uh considering the uh criteria that I showed you yesterday. But again, this is um let's say a basic situation, everything is changing if we're facing somebody with on top of the brain injury as a R DS hemodynamic instability or, or, or, or, or other stuff that most may require a depreciation. Thank you. Something more to be at. Well, I think that even in for shivering, so we we know that uh shivering must be treated. This is gonna come out also in uh, in the guidelines. But uh, as, uh, uh, the colleague was saying there is no consensus of on which drug should be used. As first line, I think that as common sense, the principle in our mind has always to be that we have to start from what is less aggressive and there's less side effects and then eventually go for more aggressive treatments. So, uh, common drugs, even you can try paracetamol, some out suggest magnesium and then opioid sedation, light sedation, which should be enough to avoid the shivering. Not more than this, we personally try to avoid neuros blockers because we know these have consequences. Despite in some cases, it's the last resource that you have, uh, a tricky question. And, uh, and then we will go out to the, the closing of this uh nice discussion. So how do you approach the patient that is nearly hypothermic? So 32 degree at risk at the end of the 1st 24 48 72 hours. Do you rewarm this patient? And if so, how do you do that? Thomas? So if, uh, the patient shows up at the emergency department and he's hypothermic below 33 we take it intentionally. We, we slowly rewarm to 3033 and then, uh, we let him rewarm and clamp the temperature at 36 because right now we're using a 36 temperature control um, protocol. Uh So we let him spontaneously rearm. This is the answer to your question. Um below 32 it's uh the guidelines say you should, you should uh take him to a safe, to a safe point, which is, is uh is 33. Um And uh if this takes a long time uh to spontaneously war from 33 to to 36 or 37 then we let it happen spontaneously and we just uh monitor. So the, the process, if this is the question, the answer you were looking for. Thank you, Daniela. What do you think is needed to develop a temperature control further? And this might be your last question to you. Yeah, that's a question. I already a little bit answered yesterday. Uh There are some gray areas, as I said, uh because uh we do not know if we can go down with the seal age. We tend to do that in the near term babies, but obviously, we cannot go very much down because we know that derm is also detrimental for uh white matter in premise. Second point is that we do not know if we can eventually cool babies that are arriving in the NICU later, I mean, after 12 hours of life. And again, in order to be um very much accurate and uh homogeneous in the population, there's a big logistic behind and um to transfer these babies to a to a hub center, as I mentioned yesterday, uh We do not know if um and how much epidemic can be actually useful for the associated diseases of parental asphyxia, meaning mecon in use A R DS, for example, or mear dysfunction. This is mainly why we use full body epiderm rather than selective head epiderm. There are some data showing an effect on these other organic functions but trial are still warranted. And finally, uh there are a number of drugs that have been associated with APIM in order to improve brain protection, but there is no strong evidence for none of them. And the studies are still ongoing and needed like for erythropoietin, melatonin, Exelon and many, many others actually, thank you, Kiara. What would you like? The people in the room go out with in their mind? I want to be very pragmatic. Uh So I would like that people go back to their words or shift and be uh very, very careful about the temperature. Uh There are good uh temperature management ways to, to deal with our patients and bad ones and it's not easy to do a good temperature management because it's not easy to manage temperature. But at least if we understand that we have to be aggressive on the treatment of fever because it really worsen can worsen the outcome. And that for visa, we need protocols, we need to agree on what to do and we need to have a strategy. There are guidelines, but then we know that in our local hospitals, we have local protocols, these should be implemented. This is to me uh fundamental in order to make sure that the patient receives the same type of care when he is admitted to the IC U and over the days, regardless the doctor who is in charge for the afternoon or for the morning. So to me uh creating a local protocol based on international guidelines is a suggestion and the message that I would like to, to provide. Thank you very much. So I need to deeply thank the three panelists for their intervention and the contribution that they gave to this discussion. Uh It has been a pleasure and an honor for me to moderate you three. And I hope that uh all the questions that were in your mind were put uh within my tablet and uh that I satisfied the curiosity of the whole of you. So if uh the uh technicians might help me, uh we close this session and we moved to the following one. So as you know, we have now the breakout sessions that will be starting. So in this room, we will have the cardio rest session. So in this plenary room, so those of you who are scheduled uh might stay in this room and the neuro session which will be led by Kiara will be at the lower level at room L three Asia B. So we will be starting in around 15 minutes. So please just have a slowly movement towards your own room. Thank you very much for being with us. Created by
