Transcript Video European Society of Intensive Care Medicine: Fabio Taccone presents Update on Temperature Control following Cardiac Arrest Good afternoon, everyone, and welcome. Uh, this is the first episode of a three-part webinar series on temperature control in intensive care, which is being held in collaboration with BD. The series highlights the critical role of precise temperature control in protecting the brain. And improving patient outcomes. Um, a big thanks to, uh, a big thank you to ASICAM for supporting this initiative and also to BD for helping spread the, the important message of temperature control as a key aspect uh of high quality care. Uh, while fever plays a role in immune response, it can also worsen secondary brain injury. Understanding when and how to intervene is a key aspect of good quality care. A recent research continues to refine uh best practices and strategies in neuroprotection. This is a 3-part series that will cover physiology, evidence and controversies. Surrounding temperature control and the aim is to offer practical takeaways for ICU clinicians. I'm pleased to introduce our first speaker, um, Professor Chris Kiara Roba. She's professor of anesthesia, uh, and intensive care at University of Jena, and she's the lead consultant, uh, uh, in the neuro ICU at the polyclinic of San Martino in Jena. She's also an associate editor for uh uh intensive care medicine and um I had a very dear friend of mine. Uh, fittingly, Kiara has a bad cold and a fever today, uh, which reminds us how common fever is, and, uh, how profoundly it can affect our ability to function, and we'll see how she goes. Um, Kara will provide an overview on temperature, pathophysiology and sec uh, in secondary brain injury. And, uh, she will explore, uh, and explain how fever can be both a necessary part of immune response, but also a harmful factor in brain injury, and how and when controlled nothermia or therapeutic hypothermia should be considered. Next, I'm honored to uh introduce uh Professor Fabio Tacona. Fabio is the head of intensive care at Brooke's University Hospitals and he's also professor. Uh, of emergency medicine, uh, at the university live of the Brook cell. He's also chair of EIEM. Uh, both Professor Roba and Professor Takone are world-leading researchers in critical care. Uh, and I recently had the privilege of, uh, working with them, uh, on best practice recommendations for temperature control following acute vascular injury and traumatic brain injury. Today, Professor Takone will share his expert insights on key controversies in temperature control following cardiac arrest, and how we should apply this knowledge in daily clinical practice. The session today is interactive, so please submit your questions throughout. And we will address them uh in the, in the final quarter of these hours. Once again, I would like to thank EIEM and uh BD for their support and to thank you all for joining us. Kara, the audience is yours. Thank you very much, Andrea. Thank you to all of you and thank you for the nice presentation. Again, as Andrea said, I apologize if my voice is a bit weird, but I have a cold and fever, but just because I wanted to get more into the topic of today. So, um, my presentation today will focus mainly on a part of physiology and the reasoning. Behind why we need to be very careful about the control of the temperature in the ICU in brain injured patients is something on which research is trying to really move on. Different pieces of the puzzle have been set, but there are still some missing links, and this is why research on this topic is so so important. So first of all, why do, why does temperature matter? Um, it does matter, first of all, because it's very common in the ICU. It's probably one of the most common symptoms in our patients. Uh, this is a, uh, a study which demonstrated that nearly half of brain injured patients developed fever. But the difference between brain injured patients and non-brain injured patients is that there is a, a number of patients who have fever related to infections. But probably the majority of this is not related to an infection factor. So it is actually true that we need to realize and sort out any infective disease underlying the development of fever, but we also have to consider that there are mainly two different ways through which there is the development of fever. One again is related to the microorganism. Toxins, etc. which causes the release and activation of oxy, microcytes, and pyrogenic cytokines. But the other one is a direct circulating release of cytokines which affect the prostaglandin which are synthesized in the hypothalamus. And in brain injured patients is probably this the one, the type of uh mechanism which better explain the neurogenic fever. Uh, and why do we have a release in brain injured patients of cytokines and an effect in deregulation of the hypothalamus? Because every time there is a brain injury of an ischemia, there is a damage in the neurons, and the hypoxic neurons develop in anaerobic metabolism, which causes the release of glutamate and intracellular. activation. This causes the activation of lytic enzymes which basically develop an inflammatory effect which causes alteration of a tight junction, activation of a complement, pro-inflammatory cytokines, which not only remains into the brain but which then develop all over the body. So, at the end of the story, this is the, the sense and it is the uh indication of a systemic pathology. Uh and uh clinically speaking, is this important? Yes, it is very important because the development of fever, this is a very big meta-analysis, more than 14,000 patients. The development of fever is importantly associated with worse outcome. Any type of outcome from the ICU length of stay. To the mortality, to the neurological outcome, according to the different scales that we have available. And why is that? Well, because at the end of the story, what we know when we have a brain injured patients is that these patients arrive with a primary damage, which is this one. There isn't much we can do on this, uh, primary damage. How our work is to reduce or, uh, avoid the development. Of secondary brain damage and fever importantly affects the development of secondary brain damage because these areas here are areas where the normal pathophysiology of compensation and of coupling between flow and metabolism is importantly impaired. So if in normal physiology, we have a preservation of a coupling of cerebral metabolic rate of oxygen and oxygen delivery, when you have fever with an increase of metabolism and when or when oxygen delivery is compromised by different factors like hypoxia, hypotension, or intracranial hypertension, this balance can be, can be. Importantly disrupt. And uh from a normal physiology, you can see here, if you go up with the arrow, you might have, because of seizure or fever, an increase of the flow and uh if you don't couple it with an increase of the metabolism or if this lasts for too much, this is related to a status of hyperemia or of ischemia. And then hyperthermia is also an important impact on uh intracranial pressure because as we have seen, it increased the metabolics oxygen consumption and this in a long way uh term causes vasodilation, cerebral blood flow increase. Cerebral blood volume increased and therefore increased ICP. If this mechanism is altered, if this mechanism is further remained and not treated, this cause ischemia and uh increased intracranial pressure. This has been demonstrated by a number of physiological studies. The group of neurostochetti studied a lot, this pathophysiological mechanism. This is a very nice study with 18 patients where multi-modern neuro monitoring was used and where changes of uh um of the uh brain temperature were assessed and so were. Factors related to cerebral metabolism like lactate, pyro, cerebral oxygenation. And what was demonstrated in this study is that when there is pyrexia, there is a reduction in the ADO2, which means basically an increase of destruction of the oxygen from the brain. This caused, uh, is, as you can see an increase of the PBTO2. This might seem strange at the first look, but this is the compensatory mechanism of maintaining the substrate coupled with the metabolism, as we have just said. So it is basically a a compensation with, with vasodilation and therefore an increase of the PBTO2, which is of course a temporary one. And if the substrate, so if this mechanism is working then lactate part of it LP ratio remains basically constant. Of course, at the expenses of a vasodilation and therefore of increased intracranial pressure. Um, the other point. That we need to highlight is that when we measure temperature, we generally measure core or even worse peripheral temperature, but we always have to keep in mind that the real target temperature is the brain one and it's not the same as the core or the external temperature. This is another very interesting physiological study from the group of Milan. As you can see here, there is the mean temperature core and the mean. Temperature intracranial temperature. There is always always a gap of at least half degrees, and the effect of the ICP is mainly related to the brain temperature rather than the systemic temperature. So Fabio will probably then discuss how to do a good TTM, but the target of temperature is fundamental. So I think we have understood from this that In brain injured patients, we probably have to be more aggressive in the treatment of a fever because it's something that really damages the uh the occurrence of second brain damage. But according to this, we will think that uh if uh hyperthermia is not protective, is uh is a damage for the brain, maybe we should go very down with the temperature uh in these patients, so to use hypothermia. So how low should we go in these patients? And that's really hypothermia is able to protect the brain. So, uh, what we know is that there is a sign for hypothermia to reduce intracranial pressure. This is, uh, preliminary secondary analysis, uh, postdoc analysis from the Eurotherm study, which is the big, uh, phase 3 trial on outcome related to hypothermia in, uh, um, brain injury, in traumatic brain injured patients. And the science that is clearly seen in this study is that when you start to reduce the temperature, the intracranial pressure goes down. And we have understood why from the previous, uh, from the previous, uh, Uh, um, slides as you can see when you start hypothermia, there is an important difference between the temperature between ICP in the hypothermia versus versus control group. But there are also some very nice uh physiological studies which demonstrate the same things, but they also demonstrate that below a certain threshold, which is around 35 degrees, the um, the effect on the intracranial thresh is not any more. That linear, so it becomes like a sort of a plateau. And you also have to think about the metabolism because if we end up understood what hyperthermia does on cerebral oxygenation, you might easily understand the results of this, uh, physiological study from the group of Cambridge, Arun Gupta, uh, where basically it is clearly demonstrated that brain tissue oxygenation during hypothermia below 35 degrees is associated with a reduction in the cerebral oxygenation. What about the clinical outcomes, not physiology, but clinical outcomes. Here are the problems because we don't have evidence in traumatic brain injured patients of a good outcome, a better mortality or neurological outcome with hypothermia. This is a negative trial, Euro term trial, but the sign in this trial is that actually patients who were pulled down after traumatic brain injured patients had a higher number of side effects. But if we look at the structure of the study, you will see that these patients were randomized to hypothermia at a very early stage. They were randomized basically at hypothermia versus monitor or hypertonic saline. So probably it was too early to think about a treatment like hypothermia, which has some side effects. And the same is for the polar study which described and analyzed the effect of prophylactic hypothermia. The point is that I think it's a matter of timing and of patience because of course when we use hypothermia there is always a price to pay to be aggressive because there are some systemic effects, some systemic side effects, so we need to think about the right patients at the right time and this is what some meta-analytic evidence are. Just in us, if we look at a single study, we won't find an, an overall effect of mortality. But in subgroup analysis, so in patients with TBI, we've increased ICP, but especially when hypothermia is used not as prevention but as a therapeutic treatment, there might be a signal over an improvement of the outcome. So how is hypothermia recommended to be used now? As an aggressive treatment, as a tier 3 treatment. This is the Seattle algorithm and as you know, there is a star case approach for the use of different uh uh treatments for increased ACP and hypothermia, 35, 36 is. Consider it as a tier three. This is a consensus just on the ICP management and as Andrea was mentioning before, uh we have uh worked uh and he mainly worked very hard on the development of uh. Some consensus recommendations. These are the recommendations of temperature target control after traumatic brain injury, where you will find a lot of recommendations regarding the, first of all, the importance of high quality TBI care and temperature control in TBI care. The way to monitor temperature, so continuously. Core, brain, etc. the targets of normothermia, which should be between 36 and 37, and the different steps of temperature control according to the severity of intracranial pressure. So as a tier zero, just treat the occurrence of fever as a tier one. Controlled normothermia. Tier 2 controlled normothermia. Tier 3, you might consider mild hypothermia. And the same thing was done with stroke patients where basically you will find different types of recommendation regarding how to measure, how to monitoring, and how to manage shivering. And in all these, the important thing is write local protocols and. On guidelines and on the patient's needs. So it's the right time, the right patient, the right temperature control, and now I hope that I have quite nicely prepared the audience for Fabio. Andrea, thank you very much for this opportunity. I thank my group in general, the group of Cambridge, uh, of the NCCU and uh the and Nick section of of in general. Thank you. Thank you very much, Kiara. That was a fantastic presentation. And uh now I leave the floor to Fabio and uh uh please um put your questions to be addressed at the end, we'll have 15 minutes to discuss. Hi, Andrea, and uh hello to everyone. Thanks, Kiara also for the nice introduction. I hope you can hear me and see my slides. I was waiting for your introduction, but in the meanwhile, I received a call from the hospital, so I had to disconnect. So, we start my presentation focusing on cardiac arrest. This is my conflict of interest. It is important for everyone to know that I've been giving lectures for BD and all that produces um temperature um device. So that's very important for everyone to know when I start my presentation. Um, the hypothermia story in the field of cardiac arrest is not a recent one. It's been started a few decades ago with uh Peter Safari. Before Peter Safa, already people in the US reported the use of hypothermia for inhospital cardiac arrest with, of course, as all cases serious, the bias of reporting positive results. And we had a lot of investigation first in the experimental field. And then in the human field showing that, you know, cooling down patients suffering from post anoxic brain injury was possible. And as uh Ciara has suggested that the potential for neuroprotection was also, um, quite, uh, interesting for these researchers. So that randomized clinical trials were conducted. In 2002, published in New England Journal of Medicine with positive results and then this has led to introduction of the hypothermia as a neuroprotective strategy in patients suffering from postsynapsic brain injury. It was so uh well used that uh if you are a fan of Star Wars, you know, that, uh, uh, Captain Han Solo was also cooled down in Kryptonite during one of the episodes and then he was there for 72 hours with a good outcome. But in general, many uh journals have reported repeatedly the use of hypothermia as a safe, uh, life saving therapy for patients suffering from cardiac arrest. That's why this therapy has been used for decades in most of survivor after cardiac arrest. But of course, the literature has evolved and we have understood that that the evidence behind this recommendation was potentially weak. Which led in 2013 to the publication of a TTM1 study comparing, let's say the standard 33 degrees temperature hypothermia with the let's say a less intense hypothermia therapy, but still hypothermic at 36 degrees showing the difference between the two groups. And then at the end in 2021, basically we have repeated the first trial in 2002, again comparing hypothermia with control normothermia. And this has led to the publication of this large trial, TTM 2, summarizing this cartoon where almost 2000 patients were randomized to hypothermia 33 degrees when compared to control normalthermia. And you can see there were no difference in mortality and the occurrence of poor outcome between the two groups, which basically uh changed the way that uh the evidence has been, as, as was, was suggested so far. And uh Most of the people has recommended a shift in practice, so we have moved from 2003 ILO recommendation, do it for everyone, cool down all cardiac arrest survivors to 2023, where there is basically no more place for hypothermia in the management of such patients, but still with some people who do not or not convinced of a so strong recommendation in that direction. Now, if you are a fan of meta-analysis, these are the three most relevant ones following TTM 2 publication, the one here from ILO, Classical Systematic Review meta-analysis. The second is a network meta-analysis which looked at the different levels of hypothermia compared with different levels of temperature in the control group, also including controlled nomothermia. And of course, it's a modern approach of Bayesian meta-analysis, the tree were concordant to say that there was no benefit in terms of mortality or neurological outcome when patients were treated with hypothermia when compared to normalthermy. But still there are a lot of criticism in that. There are still people do not believe that this is over, and there are a bunch of arguments that we raised during Congress and pro-con debates on why this conclusion should not be so strict. Now, one example of these controversies come from uh uh guidelines. So these are the guidelines that was part of, uh, from the ERC and the European Society of Intensive Care Medicine which recommend actively preventing fever in postcardiac arrest patients. Basically, they recommend to put the patients in the, let's say, nothermia group of TTM2. Now there is a second guidelines coming from the European Society of Emergency Medicine and the Society of Anesthesia intensive Care that suggested that 32 to 34 degrees of hypothermia was still possible for patients after cardiac arrest for 24 hours based basically on a Cochrane review published last year in the Cochrane Library. And finally, when you look at the American recommendation for American heart, they say, basically, you can choose between 32 and 37.5. Basically, whatever is the temperature you choose, the outcome potentially is the same for patients. And it's quite a little bit, uh, you know, challenging for clinicians to having Experts from different societies looking at the same literature and coming out with three different recommendations that are not uh convergent. It's a, I think it's a little bit tricky when you want to translate this into your clinical practice. And to me, it's a little bit like a war between believers and non-believers. And as you know, in medicine, we cannot just believe what we think is correct. We have to demonstrate what is correct for patients, and we should probably be more uh Practical in the way that we interpret the uh existing evidence in that field. Now, just to discuss with you briefly some of the criticism that have been raised during the last years on that topic. People say, you know, TTM 2 does not represent a population of cardiac arrests we see in the daily life because these are patients who have a bystander CPR, uh, 75% of shock algorithms. They have a lot of uh ST elevation, macardial infarction. If you see data from US. These are data from, you know, again, the American Heart Association. Most of hospital cardiacs are not witness. Most of these patients do not receive a standard CPR. Most of these patients has no shockable rhythms, and the stemmi is only 9% of patients. So you might say TTM 2 is a great study but does not represent the patient population that I will treat for these patients. Maybe hypothermia is still effective. But I have to remind everyone that the only evidence suggesting that hypothermia is effective is absolutely not in that population we will observe in the US, which means no shock algorithms with no stemmy, whatever. The only evidence we have is no selected patient population of patients suffering from out of osteocardiac arrest with bystand with witness arrest, and with only shock of a rhythm. So we cannot extend. Uh, that limitation of TTM2 saying we should use in other patients that therapy for which this was not demonstrated. The second criticism is that, you know, TTM2 was not reproducing exactly the same patient population that the first to try is 2002, which were more selectively choosing some cardiac arrest patients and saw that the fact that the population was not the same could explain the differences in the final results that we have observed. Well, we have published recently this secondary analysis of TTM 2 where we have selected patients who had the same characteristics than the original ACCA trial. This is the temperature curve and you see here 600 patients, twice the number of patients included in the original ACCA trial and When you see the results, what is very interesting to know is that now 70% of these patients survive with Gatcom in 6 months. So we have really improved the care of these patients. It was 50% in 2000, it's 70% now, but still no difference between the two groups. The third point is that, OK guys, it's not only TTM2, we have other studies like Hyperionion from France looking at no shock borihythms. We have maybe in hospital cardiac arrest where there might be a place for hypothermia. This population were not directly included in TTM 2, and there are some other victims of cardiac arrest who have no criteria matching with the TTM 2 trial. Just for no shock algorithms, I remind to everyone, we have combined the Hyperion study and TTM2 with no shock borithms, and we have shown that there is no difference in outcome and mortality or neurological outcome when you put all this non-shockable rhythm together. So I think that the initial rhythm observed after cardiac arrest is not a good way to select patients benefiting from lower level of temperature. And if in hospital cardiac arrest is a target population, well, we don't know, and there is the ongoing IHTTM study about to start in France and Belgium that will try to respond to this question in the next years. Other question would be how we selecting the right population? Maybe patients without by standard CPR lacking this uh um systematic review meta-analysis could be a population where there is enough brain injury where using lower temperature might be effective, but still, we don't have the answer. And uh in ECMO is the same questions. You may are aware of the Hypo ECMO trial conducted in France, uh, testing the hypothesis that the hypothermia could be beneficial in patients undergoing the VA ECMO. And then they performed a secondary analysis of patients suffering from cardiac arrest and then put Ovemo for a cardiogenic shock following cardiac arrest, where in this patient population sappothermia was associated with lower mortality, but again, most of these patients were in hospital cardiac arrest. And again, they only show difference in mortality but not in neurological outcomes. So it's still something that is not uh well defined. It should be further evaluated in more uh dedicated trials. Now people say, OK, maybe this doesn't work because in TTM2 trial we were too long to reach the target temperature. It took a few hours. We have to start hypothermia before hospital arrival. And again, remind to everyone, when people have tried to cool patients before hospital admission using cold fluids, the results were absolutely not in favor of doing this kind of approach, so early hypodermia with cold fluids to reduce the time to target temperature. Other people say, you know, the TTM trial is a trial, but it does not uh replicate real life because we have plenty of observational trials that have shown that maybe hypothermia works. This is true, but again, it's just a slide I've tried to prepare for this. Presentation. There are many trials that have showed that hypothermia might work in registry, but some others who have shown the opposite. So claiming that no randomized trials should be used instead of randomized controlled trial is still not a good point. And then don't forget that as Cara pointed out, hypothermia is not an easy to perform intervention. There are side effects that we need to monitor. Some of those we can control, some of those we can less properly control or they still occur and then maybe can. create the problems in our fragile patients. And don't forget also that the quality of the methodology of the initial trials that were published supporting the use of hypothermia was not the one that we should require today to publish a paper in the New England Journal of Medicine. These are some of the characteristics and pointed out that, you know, some of these trials would not met the criteria of a high quality methodology for the mass clinical trial today. And probably one of the limitation is that we were not able to translate what the lab has told us about the feasibility and effectiveness of hypothermia in humans because the complexity of the human setting is not the same that the very well controlled situation in the animal lab where animals are often healthy, where hypothermia can be provided early in a very well controlled fashion without multiple organ dysfunction. So this is a limitation of the non of the limitation translation of the results into human setting. However, there are some ongoing research that will provide additional questions to that field because TTM 2 trial is not the only trial, is not the final response to our questions, and we still need the research to understand which patients can still benefit from different kinds of temperature control in that field. In the meanwhile, what to do? Well, one message for me is not, you should not stop caring about controlling temperature in these patients because abandoning TTM is not acceptable. If you want to reproduce the same results, the TTM 2 in the control group. You need to sedate these patients, provide strict normalmothermia, and use a temperature feedback device. This is what has been used in the TTM to trial, which means active therapy, not to leave the patients in the bed and doing nothing for two days. If you want just to use the drugs like for example antipyretic therapy, this is not effective, and using antipyretic therapy will not be able to reproduce the same results that the temperature feedback device as has been shown in the TTM 2 trial. So these are the kind of devices we have available today. Some of those like this one using, you know, gel circulating system or intravascular catheter, have the capacity to adjust themselves and to reduce the nurse workload and to adequately keep the patients within the target levels and hold also controlling rewarming, also controlling the post-TTM fever. So these are the ones that provide the most effectiveness in terms of TTM metrics to provide adequate temperature control in these patients. Thus, the use of the selection of the device will impact the outcome of the patients. I just mentioned here 3 systematic pre meta-analysis that have shown basically. That the most sophisticated is the device you use to provide TTM after cardiac arrest. The highest are the chances of the patients of good outcome, either mortality, either survival, or neurological outcome. Of course, the limitation of the tree meta-analysis is that the most, most of the trials that have been included are observational, retrospective, or prospective studies, which of course limit the strength of the message coming out from these meta-analysis. And clearly we have only 4 randomized clinical trials. Uh looking at one device versus another strategy which do not provide enough patience to conclude definitely on the use of the optimal best device in that field. Still, if you want to see that, just follow the guidelines, you need to control, monitor the temperature as the Kara pointed out. But today, you should provide controlled nomothermia and whether there is a population of patients who might benefit for lower target temperature is impossible for the data we have today to identify those patients. So you need a protocol. You need a protocol even if you target the control nemothermia, which includes continuous measurement of temperature, as you heard from Tiara, using the core temperature because you want to cool and protect the brain. You have to start as soon as possible as per hospital hospital admission. Use devices because you want to reproduce the same result and TTM2 control group, uh, provide with sedatives and analgesics because the device alone will not be able to counteract. The mechanisms that are being initiated to bring the temperature up after brain injury, you know, you have shivering because the temperature of the brain is set up in higher levels than normal values. You have to use sedatives and agentics in the field, consider complication and all the changes associated with hypothermia. If you're targeting hypothermia, define targets, and of course, provide the good quality of TTM. That's a good point because we have tried to discuss this and present as a nice picture. What is a high quality TTM to me is having the patients where the target is defined. You have a continuous core temperature measurement, you have a device able to rapidly induce hypothermia, reduce variability. Provide a slow rewarming if possible combined with a good protocol of sedatives and analgesics, and then you have a fever control after the initial phase. This is what I would call high quality TTM when compared to a system where you're still trying to change patient's temperature by in the way that is uncontrolled or well less controlled with the intervention that are not so effective. Of course, there is some, uh, that is still important to uh discuss in the, in, in the future of, of, of our research is that we can easily understand that one intervention cannot fit and be effective in all patients. So, in the future, this is something that we know from the sepsis in RDS, for example, we need to identify those who are TTM responders, which means those who have the highest benefit after cardiac arrest to be cooled down to a lower temperature when compared to normaltermia. And just to summarize, it's just an idea and we conclude with this, we should probably identify patients not based on the disease. So having a cardiac arrest is not enough, but they should have a cardiac arrest with some degree of brain injury that justifies the use of a neuroprotective strategies. If you have a patients after cardiac arrest who is too well, for example, the guy. was a very short VF, immediately resuscitated, sedated by the ambulance, arriving at this hospital, moving and fighting against the ventilator, maybe with a very normal EG at the beginning, this patient doesn't need any sedation. He will do probably well regardless of the temperature control. On the other side, if you have a patient who is too sick, very prolonged cardiac arrest. No flow, which is unknown, very long, no flow, low flow time, maybe hypoxic hypoxic injury with the bilateral absence of a light reflex or the beginning, no spontaneous breathing, fixed pupils, maybe other characteristics looking on brain imaging. Maybe these patients are too sick. Whatever you will do is not the temperature. We change the extent. Of a very severe brain damage. All the others could be in the future randomized clinical trial where with the presence of, uh, let's say a mild brain injury after cardiac arrest, still salvageable, then testing the hypothesis of apothermia versus normothermia should make sense in again in randomized clinical trials. So to conclude, Uh, you know, you heard that brain injury is irrelevant. It's the first cause of death after cardiac arrest. Temperature control is very relevant in the way that we manage these patients. To me, the current evidence suggests That we should aim for strict, active normal term. I think words are very important, so we, we try to target temperature below 37.8 with an active intervention, including also temperature feedback devices. I think that hypothermia cannot work in all patients. I'm almost sure, but we probably need to make more research to understand the future whether there are potential responders to a hypothermia and when we have identified these potential responders testing this kind of population in future randomized clinical trials. And I think this was my last slide. I'm very happy to have been part of this um Uh, of this, uh, uh, today meeting, and I'm happy to take any questions. Thank you. Thank you, Fabio for a fantastic presentation. Uh, there are some questions from, uh, uh, the, um, Uh, listeners today. Uh, the first is for Fabio, asking whether you think that hypothermia will be recommended again, uh, in the new ERC guidelines in 2025, and if so, to what degrees Celsius? Yeah. Honestly, this is a good question. I have to say this time, I will not, I mean, I don't think I will be part of these guidelines. So there will be other experts in the field. I don't see the literature has changed so much from 2021, so. Considering the way that um ERC and ACMS work in the past and that the guidelines in 2021 were based basically on TTM 2. Um, I presume that it will be in the same recommendation to provide the temperature control within the uh control group of the TTM2 trial. Again, I think it's important for the, for the people who are now listening to us to understand. That to me what is very striking in having 3 different recommendations from 3 or 4 different scientific societies looking at the same evidence. This shows that there might be controversies, so different point of view, that the way that we do guidelines is not exactly the same. Maybe it depends on a lot of what you think about this issue. But considering the European Society of Intensive Care, I presume that there is no reasons why the, the recommendation should change considering that the literature has not really changed since 2021. Excellent answer. I, I wanted to ask uh uh something about uh the neuro monitoring in um survivors of cardiac arrest coming to the ICU. Is there any role for it and how do you rationalize your approach to it? Oh, thank you for this uh question. I think that uh Fabio has already highlighted the fact that the majority of patients with uh after cardiac arrest then die because of uh cerebral reasons and most of all because of uh cerebral edema. So sometimes what I, I say or I think is that uh we consider cardiac arrest patients like a sort of a general IU patients, but at the end, they are neurocritical care patients and that's probably the truth. Um, the problem is that regarding monitoring, we don't have many uh evidence, especially for the invasive one. What I can tell you is that if a patient allows it, uh, the clinical assessment in general is the best neuro monitoring that we have available. There is not any monitoring in the world which is as precise as the clinical assessment of, of a patient. So if possible, the patient should, uh, uh, should be woken up. If possible, means, basically, if we follow the guidelines for, for sedation, there are not many reasons not to wake up patients. The reasons are intracranial hypertension. Uh, status epileptic or um different crop prices and, uh, ARDS when you have a patient who uh is difficult to be ventilated uh and needs paralysis and therefore a sedation, and some cases of parasympathic hyperactivity where you, you really struggle with uh, with this condition. But apart from this, in theory, there are not big reason not to, to win or stop the sedation. Having said this, as you all know, I am a fan of uh the neuro monitoring tools. So, yes, the answer is yes, I do use neuro monitoring. In these patients, I use mainly uh non-invasive neuro monitoring tools. Um, you have probably read, and you know that there are different studies on the use of veneers, especially from the Finland Finnish group, which then one of the studies then raised the software regarding the target of CO2, which then led to the to the trial regarding the brain perfusion. Personally, I'm not a huge fan of uh of veneers because I think that from a methodological point of view and technical point of view, it has uh many sides of many confounding factors, especially extracranial, um, extracranial blood flow. Uh, but we have it and, uh, and we use it. Well, then we use a lot of transcranial Doppler to adapt the perfusion and to assess the ICP noninvasively. We use optic nerve, sheet diameter ultrasound. We use pupillometry, and we use quantitative EEG. These are the plethora of monitoring that we use. Uh, we don't use the invasive monitoring in these patients, but, uh, especially in Canada, there is the group of, uh, uh, Mindersecon who is, uh, uh, another Cambridge, uh, uh, alum. Uh, and, uh, he has done a lot of research regarding the use of invasive ICP and PBTO2 in these patients. And actually the results are that, uh, many of these patients have increased ICP or uh reacted PBTO2 and probably therefore needs uh uh sort of uh of treatment. So I think this is the next uh pathway to explore in terms of uh research. That's very clear. And, and now a question for uh for both of you. See the controversies as outlined by Fabius's excellent lecture. In practice, uh, what do you do when a patient comes to your intensive care unit? That's a, um, that's a very good point, uh, you know, uh, yeah, because, uh, uh, I think that what we have the chance, uh, to have in my department is that we participate to different clinical trials. So basically almost all the patients who suffer from cardiac arrest, either out of hospital or in hospital admitted to our ICU. Uh, are now included in a randomized clinical trial, which will basically uh help the clinician to decide. It's not our decision is the computer or the randomization system, which decides. Outside that, what we have, uh, recommended to clinicians in the past before these trials is the most important thing is that temperature should be monitored. And then you need to set up your temperature levels. So all the patients who came into the department had a temperature target for the 1st 24 to 48 hours, and then you adjust the therapies, the sedation, the analgesics, and the devices according to that uh levels. In the last years, we have more and more patients being treated with controlled normothermia, as in the TTM2 normothermia group. Uh, than before, because before, before 2021, I would say most of our patients were treated at the hypothermia at 33 degrees. OK. And uh does that translate in uh what percentage of patients being uh treated on automated devices? Well, again, this is, um, a decision, uh, via characteristics of our department because we are very much into the controlling of secondary brain injury with a lot of, uh, non- anoxic brain injury. We had a lot of devices in the department. So basically, all the patients receive, uh, temperature feedback device, most with the surface system, some with intravascular, but we basically treat, uh, all of them with the temperature feedback device. When Kara, could you share your experience of uh in practice when a survivors of cardiac arrest comes under your care? What do you do? So, uh, I think that Fabio probably has the ideal uh uh situations and uh maybe my center, but probably Italy in general and many other countries are not like, uh, uh, do not have all these availabilities like we do have feedback systems, but, uh, not. As much probably as it would be needed. Um, the point is that in our center, we are changing practice because before there was a lot of, um, clinical, um, uh, clinical use of pharmacologic therapy for, of a fever. Uh, which, uh, the, the problem with pharmacological treatment is that, uh, at the end of the story, if you have an acute patient with brain injury, you end up then using an automated device but that in the meantime, you, you lose hours of, uh, of fever because in many, many cases they, these do not work. So basically we reserve immediate automatic device treatment, especially in patients in the very acute phase with very unstable intracranial conditions, and in these patients we rarely start pharmacological therapy. Now, uh, because what we have seen, but it's also what, uh, uh, the liters, has seen is that, uh, uh, you lose most of the time you, you, you lose time and, uh, with fever time is brain and um, it's not like in the general IU population. Temperature doesn't forgive you, uh, when there is a brain injury ongoing. So I think we need to be quick. Thank you very much. That's, that's very clear. In terms of, uh, um, setting targets and strategy, obviously, you have centers like Fabius, um, and uh for our team in Cambridge, we would have a similar attitude to temperature control and be quite aggressive, uh, using, uh, um, target control in the vast majority, if not the totality of patients. Generally, in our case, uh, set to control northermia. But, um, I, I'll ask you both, is there uh any scope, either for clinical practice or strategy or for research to stratify patients depending on the level of injury that you suspect that they might have suffered, and then titrate the, how aggressive your care is. Um, either as part of daily practice or perhaps as a, uh, as a research framework, but rationally it seems reasonable to say. Uh, as Fabio presented earlier, if there are patients that have a, a minor insult, you, you would want to wake them up and, and give them something to eat. Uh, but if they had a profound injury, you might want to keep them asleep, uh, and perhaps at the very least with control hormothermia, but perhaps they might benefit from mild hypothermia and swelling is going to be. Precipitating secondary brain injury. Soabbi, how do you go about that? Um, so, uh, there are a few, uh, analysis in the literature that is, um, that have associated the severity of the patients. Basically a combined score of uh Uh, hemodynamic and neurological injury based on very, uh, easy variables. Basically, the Glasgow or a full scale compared with some hemodynamic parameters or some others looking at lactate on mission. So those who are most severe injury after cardiac arrest would benefit from lower temperature, which again to us makes sense because these are the ones with the most severe injury where, you know, neuroprotective strategy might, might work. On the other side, when we try to replicate. The same kind of analysis using the databases from the randomized clinical trials. We're not talking about the registry where the use of hypothermia, there is not aquipo at the moment of use because you don't know why the patient is exposed or not to hypothermia, but we use the database. We stratify the patients according to different score of severity, and we try to replicate this data. This is not the case. So again, Um, and the, the severity of the patients, or at least the score that we have available today. Do not seem to be adequate to separate or to identify subgroup of patients who might benefit from a different strategy of temperature control. That's why I'm saying probably early neuro monitoring, which will more adequately assess the severity of brain damage, including early G, maybe pupillometry, maybe a Doppler. I don't know if biomarkers could be adequate enough in a very early phase, could be useful. To identify these patients with the some existing brain injury and being randomized in the future randomized clinical trial. At the moment, all the research we have supporting this idea is based on registry analysis, which are not being reproduced in the analysis of databases from randomized clinical trial. Kiara, any comments on this? Uh, I totally agree with uh Fabio's view and, uh, with, uh, the literature that he mentioned that. I just want to add a pragmatic comment. Very often you find yourself maybe in these situations where uh you have a patient who is waking up, so you want to wean him from the sedation. And this patient developed fever and now you have two ways. One way is to treat the fever with the risk that you have to sedate him and put him again to sleep so you don't have any more of a neurological assessment or leaving, waking up and uh uh and uh do not treat fever or do not treat it, uh, properly. Uh I don't think that is an answer. A true answer based on literature on this, but there is a a common sense and there is uh uh the path of physiology because as we always know, guidelines uh and literature may change, but the part of physiology never changed, no. Uh, I think here the reasoning is about, uh, uh, which is the stage of a brain injury and the risk of secondary brain damage of a patient. Uh, you might also, in some cases allow the patient to have a slightly higher temperature than you will want because he's in a. Chronic phase, not more in, in acute risk of secondary brain damage. Or the other way around, you take the responsibility to put him again under sedation because you feel that in that moment, it's more important to preserve the intracranial physiology. Um. Very good. Thank you very much, yeah. We have some more questions, uh, uh, and time to address them. Uh, one commentator states, uh, in the TTM2 study, there was, in fact, a 2% higher mortality in the 33 degree group. This was not significant, but the difference of 2%. Means the number needed to harm of 50. This is very worrisome to me. Do, do you guys want to comment on that? No, I mean, um. How to say that, uh, politely, I would say we, we, we need a little bit to, to be less trialist and more clinicians. So there are some trials have been done looking at the modern methodology to respond to a question. And the, the, the TTM2 trial have responded to a very relevant questions whether the use of hypothermia would improve mortality and neurological outcome when compared to controlled nomothermia in that patient populations. We have now the response. Now if you want to comment on 2% and the minimal clinical difference between the intervention on our patients. And we should consider maybe a larger court of patients where this 2% could be really be confirmed and not overemphasize with the study has not been tested. That's why I'm saying, you know, I agree that there is to me from that trial, no reasons why you should still use 33 degrees. So I agree with the, with the person who made the questions that, you know, there is no signal in favor of hypothermia. Whether now the study showing harm of hypothermia, I'm not sure we have the right methodology, and this was not the question of the trial. And, and, and also for a, for, from a purely methodological angle, the 2% difference uh comes with um confidence intervals and these confidence intervals overlap. So there is that's why I'm saying, you know, Andrea, I think we know, I, I, I, I like, I understand the concept that everyone knows, is, is in favor of understanding large on the clinical trials with the great methodology, but we need also to understand which is the clinical questions that the, the study can respond. Yes, but not to response more than the questions why the study has been um formulated and, and, and I think this was the response is quite clear, but I don't see the harm. In that study, and there is no seen signs of arm in all the systematic review meta analysis have been performed in that field specifically for non-anoxic brain injury. I concur wholeheartedly. Uh, there's another interesting question, uh, or a series of comments about how do you think withdrawal of life support could have impacted hypothermia trial outcomes? Um, since withdrawal of life support is in fact a predominant cause of death in, uh, this patient population. Uh, one of the commentators is asking, what if we got it wrong in some patients. And some other commentator, uh, says, uh, that, uh, agrees that the withdrawal of life support is a key aspect to understand this data and the natural history of the disease, of course. Uh, um, and it states in TTM2, this was done by assessor blinded to treatment. At, at the time point later on 72 hours. If you look in the supplement, there was no difference between groups. Again, I was part of TTM2, so I can start with the response. I would say that this is a very important question. All the study on cardiac arrested in general, all the studies looking at an intervention on brain injury patients can suffer from this self-fulfilling prophecy uh limitation. Um, the, the, the reasons so let's say the, the, the prognostic algorithm used in the TTM2 is very close to the actual recommendation of the AI guidelines to prognosticate. And there are at least two publications cramming from countries where the prognostication, the withdrawal of care is not possible, showing that the false positive rate of these guidelines is 0%. So, um, I would say that with all the, the fact that we can still wait more and be more conservative and keep the patients alive for 345 weeks to be sure that the brain damage is still almost irreversible. The, the protocol used to limit, to withdraw life sustaining therapies and TTM to trial is probably a very good one when considering the actual literature. Of course, the outcome assessor being blinded also allowed to reduce the bias related to the investigators to favor one group on the other, limitating or withdrawal life sustaining therapies in one randomization arm and not in the another. So that's also to me very important. The methodology was very strong and well conducted. I cannot, uh, I cannot, of course, reply how many patients would potentially be waking up and which we kind of brain damage if we have waited for 6 months to everyone. I think this is not the, the, the, the, the, the response would be, be, before that, uh, be behind the study. And, and the, the, the way that the withdrawal care was provided is almost in line to the recommendations. So I don't see any limitation in that, in that approach. Thank you very much. That's very clear. Uh, this brings the first, uh, target, temperature target control, uh, webinar episode to an end. We thank you very much, Fabio and Kiara, for, uh, uh, your excellent contributions today. We have, uh, uh, 2 more dates on the 17th of April. Uh, uh, we will, Kira and myself will be introducing, uh, um, Raymond Hellbo. We'll be discussing temperature control, uh, following vascular brain injury. And later on, on the 26th of June, we have, uh, uh, John Coles, um, who will be discussing temperature control following traumatic brain injury. I'm aware that, uh, um, uh, many people had issues with, uh, connecting to the webinar today, but I hope this will be available offline, uh, at a later date. And, uh, once again, thank you very much to AIM, and for, uh, uh, BD, uh, to make this happen. Thank you very much. Have a good evening. Thank you. Bye bye. Thank you. Created by
