Transcript Video Temperature Control in ICM: Vascular Brain Injury Speakers: R. Helbok, A. Lavinio Moderator: C. Robba 16:00 – Introduction by A. Lavinio 16:15 – 30-minute presentation by R. Helbok 16:45 – Q&A session led by C. Robba Ladies and gent, good afternoon. It is my absolute pleasure to welcome you to this webinar, which is focused on temperature control management. As you know, this is the 2nd episode of a series of 3 webinars which are focused on the temperature management in the intensive care unit, and in particular in the neurointensive. patients. In January, we had the first meeting online. The webinar was mainly focused on pathophysiology of temperature control and management in patients after cardiac arrest. And today, we will focus mainly on cerebrovascular disease, while I would like to remind you that in a few months, We will have the 3rd meeting which will be focused on traumatic brain injury. First of all, let me thank SICM and BD for supporting these events, uh, for supporting uh organizing these webinars. They, thank you very much to all the organizing team, the technical staff, and the company. Uh, and now I think it is time to introduce you the speakers and the topics. I will start with myself. I am Kara Roba. I am a professor in anesthesia and intensive care at Genova in Italy. I'm the past chair of the neurointensive care section of, of SACM. And my research is mainly focused on the management of brain injured patients. But together with me, we have two much more important speakers. And the first one that will, uh, start with, uh, uh, this webinar will be Doctor Andrea Lavino. Andrea Lavino is a consultant in the new ICU and affiliated assistant professor at the University of Cambridge in the UK. Uh, Andrea is a longstanding, uh, has a long-standing interest in the temperature management and he is the leader and first author of the two consensus that we have recently published on the management of temperature in a traumatic brain injured patients and cerebrovascular disease. He has a lot of collaboration with industry to develop new solutions for the management of the temperature, and he is editor for Journal of Critical Care. Um, Andrea will start with a presentation mainly about putting the topic in the contest, uh, part of physiology and the importance of temperature management. Afterwards, we will have a Professor Raymond Hellbo. He is chair of the department, uh, from the University Hospital of Linds. In Austria. He is a professor. He's very active in the SICM uh neurointensive care section, and he's a great expert in cerebrovascular disease. So I think we are very lucky to have these two speakers today. Um, just a couple of reminders, we will have the question. at the end of both presentations. Please don't forget to type your questions in the chat, and I will make sure that Andrea and Raymond will ask, will answer to all your questions. I think this is a very important, uh, uh, webinar, uh, as we have also seen from the first webinar, the The importance of managing, monitoring temperature is fundamental in the ICU and in particular in brain injured patients. In this case, we will focus on subarachnoidal hemorrhage patients, ischemic stroke, intracerebral hemorrhage, and we will go in deep regarding the new guidelines, clinical applications, and the pathophysiology. So, I don't want to Waste more time for uh for the speakers, and uh I will ask Andrea Lavino to start his presentation on the pathophysiology and relevance of temperature control in critically ill patients. Andrea, thank you very much for being with us today, and the stage is all yours. Thank you very much, Kara. I hope you can all hear me clearly. Um. So, um, uh, first of all, a declaration of interest, I've been working with the academic institution and industry on, uh, temperature control, and today we're particularly grateful to BD for supporting this webinar series. This is part of a, a, a broader, uh, body of work, uh, that myself, uh, Professor Hellbo and Professor Roba, um, have been working together again, supported by BD that culminated in the publication of a consensus recommendation in critical care last year and in the British Journal of Anesthesia in 2023. And Professor Albo will do, uh, uh, uh, will offer a deep dive into those, um, in particular, obviously, vascular brain injury and temperature control um in the main lecture today. Uh, what I wanted to do was to offer a first principle perspective on the importance of temperature control, uh, as a key vital parameter, uh, in high quality intensive care medicine. And the, for me, the greatest educator in physics, uh, one of the most, most beautiful men to ever exist. Richard Feynman explains it beautifully, and there is this BBC series, it's fun to imagine, uh, where it explains what temperature is. And, uh, he, he explains how everything that is, uh, from a cup of coffee on a table, uh, to a human being is made of atoms and they jiggle. And uh temperature is a measure of this jiggling movement, uh, of the, the, the formal way to say it would be temperature is a measure of the average kinetic energy in a system of molecules. And uh the way we define the centigrade is that if you cool down. A glass of water where crystals congeal and ice forms, we call that zero. And then if we heat, uh, a glass of water to the boiling point, we call that 100, then we put mercury in glass and divide that by 100, and we call that a centigrade scale. And obviously, the human body is controlled in a very, very narrow range within that scale. Uh, and that's extremely costly in terms of energy to maintain such a precise control. Uh, but we've all experienced, uh, at least in the mild, uh, ranges, how uncomfortable it could, it can be to experience hypothermia. And in the mild range, they indicated with the yellow colors between 35 and 32. We experience uh a discomfort, we start shivering, and there, there are compensatory responses such as increased metabolic rate, but also we seek heat, we layer up and then these are called behavioral compensations that, that we put in place. And then after 32 and below, then compensation fails, uh and uh we develop organ dysfunction. What we see typically in ICU when we overca patients is a cold diuresis. But also, uh, uh, at lower temperature, you start to get arrhythmias and cardiac arrest eventually. And at the other end, again, something that we've all experienced is uh fever, especially mild fever, which is common. Uh, and, and we all, I don't need to describe that. We all know the discomfort, uh, the sort of fatigue, uh, and the sense of flushing or sweating we might get. And then, uh, we become severely impaired, uh, uh, impaired in our function when we go above the 40. And then for just a small increase is above the 40 range, uh, a coma is common, seizures is common. And then just at 42 degrees, we get profound dysfunction and the alteration of proteins. So habdomyolysis, muscles literally melt, uh, uh, intravascular coagulation. And just very briefly, before we move on to the application of this physiological concepts in the context of intensive care, there are deaths in the general population living at home uh for extremes of temperature in the environment. And, and if you look at the, if you look at the left, uh, you can see that mostly it's when it's cold. And especially elderly or frail, uh, um, uh, people that can't afford heating, die of cold, and that generally that the compensation a lot, long-term diseases, but there is a fraction of people that die of heat exhaustion as well. And if you look at the curves on the right, you see, for example, in Paris. Uh, or, uh, less so but still distinctively. In London, where Paris and London, where air conditioning isn't that common, you see how steep the mortality curve is when temperature exceed the the sort of 20 degree mark that's uh the, the most pleasant. So, when we are exposed to exposed to these environments where it's either uh warm or cold, the first thing we, we do, and, and that's relevant to that observation about seeking the air conditioned environment, is that we have behavioral responses. So if it's cold, we would layer up, uh, sit next to a radiator or, or, or a fire, and vice versa, if it's very hot, we would seek some water or, or, or air conditioned environment. And, and to the most basic and intuitive of understanding, if you Think about the intensive care patient comatose, um, barely covered by some uh um hospital clots. All these behavioral responses are impaired. Uh, and to a lesser extent, the other, uh, responses that allow this patient to auto-regulate their temperature are also impaired. And in particular, and this is relevant to today's, uh, um, to today's webinar, patients that have bled, uh, uh, inside the subarachnoid space or suffered the stroke, they often, often, Uh, would experience a degree of central deregulation of temperature, something we refer to as neurogenic fever, uh, which is a common, um, event and also an event that has a significant implication, uh, on their, um, uh, uh, a clinical course, and, and this states that Uh, in this patient, temperature control is key because this regulation of temperature is common and this regulation of temperature is linked to very obvious and, and impactful side effects. One of these side effects is seizures. Uh, fever causes seizures even in the healthy population, uh, in, in the pediatric population, so a healthy brain, but the amount significant fevers and they have seizures. And this is uh one of the most common uh reason for uh young patients to access the emergency department. More so patients that have a space occupying lesion or suffer the stroke. And, uh, as a slightly higher range, the way high temperature affects, um, uh, and the naturates protein, literally cooking them, and I just had a nice lunch and the, the, the meat was just done perfectly, uh, which is rare. And a cooked steak has temperatures only just above 40 degrees. In the ICU unfortunately, we see patients that reach this temperature. You see CKs, and myoglobin rising dramatically, and they have massive fatal often, uh, or, or severely severely dis debilitating rhabdomyolysis. So why is fever part of the normal response to infection? I, I think a, a, a useful uh little backstory is, uh, uh, the story of the discovery of penicillin by Alexander Fleming in 28. And um he eventually will win the Nobel Prize in 1945 for uh the discovery of penicillin and saving countless lives, uh especially during World War II where it was finally mass produced. But until the early 40s, uh um the widespread and prevalent uh uh belief was that there was no use for a Uh, what Alexander Fleming at the time referred as molded juice, which might have been, uh, a sort of a weak branding for penicillin. And, uh, around those times, the, it is an Austrian colleague that wins the Nobel Prize for Medicine, uh, uh, Julius Wagneruareg. uh, I'm sure I'm, I'm butchering the pronunciation of it. Um. But what it does is that it is treating patients affected by neurosyphilis by injecting them with malaria. Uh, the ethics of this are, are debatable, um, because the, these are psychiatric patients, uh, effectively, uh, for having, um, uh neurosyphilis. And the, the mortality at the time was 100%, uh, but by infecting them with, with, uh, um, uh, malaria, it, it induces, uh, profound fevers up to the 40s. And the first group of patients die, but eventually they find the right dosing for it, curing the majority of them. So, at the other end of the spectrum, we have hypothermia. Hypothermia as being uh um neuroprotective, and there are infinite, uh, uh, an infinite number of anecdotes. One of the best one is this story from Sweden in 1999, uh, uh, radiologist Anna Bagenhol, um, is skiing after work and, uh, she remains trapped under the eyes. And for more than an hour, and when she's fished out of the ice, uh, she has 2 hours of systole, and she has the 13 degree, uh, uh, temperature at that time. She's rewarmed, uh, on, uh, uh, caldi pulmonary bypass and she makes eventually a full recovery. And this is Uh, besides anecdotes, this is in line with what we observe and we know that in cardiac surgery, when you lower your temperature in the high teens or the low 20s, you can stop the heart for an hour and then restart it and the brain recovers, um, with full recovery. Of course, there are complications. Um, and, but we have to support this 70 plus years, uh, of, uh, of, of cardiac surgery. So, uh, this is a, a, a, a slide that's very dear to me. It's a little bit busy, but perhaps I can elucidate what it is about at the bottom. We have oxygen delivery to the brain, cerebla blah flow, and this can be, uh, impaired by, by a variety. of, uh, issues, um, shock or, uh, intracranial pressure, elevation or vasospasm or hypoxia. And on the other hand, we have, uh, the cerebral metabolic rate of oxygen, and in this case, we can modulate that, say, with sedation of hypothermia. So, when we are looking after a patient and for whatever reason, Uh, their profusion is compromised and they become hyperprofused, uh, we can, uh, be less fair and allow them to develop fever or seizures, and they will get in the area of ischemia where you have neuronal loss, or at the other end, uh, we can sort of modulate cerebral, cerebral metabolic rate of oxygen so that we can achieve couple the hypoperfusion and hypermetabolism until we can restore. Um, so, in the context, uh, uh, of, uh, uh, acute vascular injury, uh, subarachnoid hemorrhage, ischemic stroke, intracerebral hemorrhage, that it is a cascade of events, uh, that will lead to secondary neurological injury. And we can use temperature uh modulation to modulate, uh, or mitigate these effects, but how do we determine in each individual patient, uh, which will be different for a vari variety of reasons, uh, what the best target and duration of temperature is? Well, as I was saying, I'd like to go back to first principles and I, I won't be marking anything anymore, but Uh, if you're at a lower level of temperature, you know that you're reducing, uh, your brain metabolism. So if someone where flow is compromised, you might be able to have less neuronal loss. If you have a space occupying lesion, you know that you might be able to modulate swelling. And at the other end, At, at a higher temperature, uh, you know that there is a higher risk of seizures, reduced ischemic time, and, uh, increasing brain swelling. So, in, in brief, and coming to a conclusion, uh, the patient, uh, that's at a risk of herniation that has a tight CT scan or a CT perfusion scan showing a perfusion deficits, then you might want to be in the strict control normothermia or even the moderate control hypothermia. In a patient that is in a, in the acute phase of a significant stroke, subarachnoid hemorrhage, you would want to, uh, um, uh, uh, maintain them within, uh, controlled nothermia or treat fever, uh, uh, very quickly, uh, by monitoring and treating it aggressively. And on the other hand, if you have patients in your group that, uh, have infectious diseases and the physiological reserve to deal with fever, you would allow them to develop one, and monitor it. And the duration of this treatment will be determined based on case by case, uh, clinician-led judgment and informed by monitoring and imaging. So, uh, coming to a conclusion, Uh, of this introduction, and I'm delighted to introduce Professor Hellbo, who will be discussing in-depth, uh, uh, acute vascular injury and temperature control. My main points, um, are that temperature affects everything, uh, um, in, in, uh, in, in a very relevant way, and for that reason, Uh, it's very tightly regulated in healthy humans, but this terminal thermoregulation is often, often disrupted, uh, uh, in critical illness and in particular, after stroke. So, um, high quality care of these patients relies on the monitor, monitoring temperature and having individualized temperature targets. And also understanding the evidence base and its nuances, which is what Professor Helber will be uh uh talking about. And uh so precise temperature control, and the last thing that I wanted to mention is perhaps as a, uh, um, uh, a future research or something that we are working on is to try to optimize temperature control when it comes to neuroprotection, so keeping a cool head but a warm body so that, uh, there can be an immune response. I thank you very much for your attention. Thank you very much, Andrea, really very interesting uh and uh thoughtful presentation. You really have uh put us in the topic. Uh, it seems that, uh, fever in brain injured patients is a bit different from any other patients. As you mentioned, uh, because it can have not just an infectious reason cause, but at the same time, it's also very important to focus on the pathophysiological cascade that fever can cause in this population. So it's very difficult I think to understand which are the patients to treat the timing, the duration, how, uh, I'm sure that Raymond has all the answers on this. Uh, well, of course, we need a lot of research, but it's very important to discuss this. Um, and now, Raymond, I think Andrea has prepared the audience for your talk. You will go deeper in details regarding the specific population of cerebrovascular disease, which actually is a heterogeneous population. So, I'm looking forward to hear what you, you will present. Thank you. Thank you very much. So welcome, everybody. Good morning, good afternoon, good evening, wherever you listen from. Um, thanks, Kiara, for that very nice introduction and also putting all these challenges on, on my shoulder. I really enjoyed the first talk, uh, from, uh, Andrea because I, I think that, uh, half the way towards uh uh a good, um, discussion or so afterwards. I, I also would like to, to thank uh BD for organizing in the European Society of Intensive Care Medicine to put up the topic because I think the topic is, is important and especially as we have some new studies to discuss. So these are my conflicts of interest, uh, from, uh, supported also from uh companies involved in, in temperature control. I'm also involved in guideline committees. I'm a co-chair of the medical devices of, of neurological devices in the European Union. And when, uh, obviously conflict of interest. I'm, I'm head of the department and uh one of the department is, is the one where, uh, which was given our Julius Wagner Jarek, um, this is the crazy Austrian who won the Nobel Prize in Physiology and Medicine in 1927. Uh, with the syphilis malaria story which you, which you heard from Andrea. So this is on the right side. This is the Wagner Jarek uh Hospital and it's now renamed since uh 2015 to Nuromed campus in, in Linz. So, I'm gonna talk about temperature control in uh stroke patients, ischemic stroke and uh hemorrhagic strokes that, um, with some thoughts on temperature management what we understand by uh TTM. Uh, that's important because, uh, TTM was always in, in the meaning of hypothermia for a very long time and now we say targeted temperature management and there is a reason for that. Methods of temperature control, which to my mind, uh, matter. Uh, if we think about the treatment of patients. What is the optimal, uh, targeted temperature? We can also discuss about the duration afterwards, guidelines which are very poor in the recommendation and that's why we need expert recommendations which were set up, uh, by Andrea as previously pointed out. So what is TTM? TTM means controlled temperature. And I think it's very important uh to understand that, uh, temperature is, is, is a, is part of the game of our outcome in patients and it's, uh, obviously, uh, what you need is a standard operating procedure, how to control temperature and you, you have to decide whether you admit fever or you, your target is maintaining normalthermia in these patients or even inducing mild to moderate hypothermia. There are several thoughts you can consider, um, and you have to consider. So the question is, do you harm the patients by the intervention? It's very important because we have to discuss about shivering as well. Uh, what is the management load, um, by applying all these measures, what, what are the costs? This is also important, uh, for several areas in the world. And, uh, do we have certain patients subgroups who may benefit from specific interventions? This is a study, uh, where you, you see in these boxes above on the right side, uh, neurological patients and the, the survival rate of patients who are having fever, and you see the drop in the survival percentage of survival, uh, of patients, uh, having fever compared to those having nothermia within the 1st 24 hours of admission, uh, to the hospitals. And if you go down, uh, the population was interest of hemorrhage, HUTC stroke, and also TBI. So the message here is, uh, fever matters in terms of survival, in terms of outcome. Uh, obviously, uh, this is an association and no, uh, causation. And there are also other studies. This is a study from, um, Uh, from, um, UK and, and, uh, Australia, and they, we, you got the same signal, a U-shaped curve. So would we know if patients are admitted with hypothermia, they, they're in a very worst condition condition and the outcome is worse. But also you see, uh, uh, an inflection point above 38, 39 degrees, that fever is Also associated with the worst outcome in TBI stroke, but not in C CN as infections and that's, that's an important point. So, uh, especially in infectious diseases, uh, we could, we think that fever has also some uh protective effect against, um, uh, the bacteria. So why should we treat fever? Um, and this obviously can be discussed for quite a long time and I just, uh, put, put some important information here, as you also heard, uh, in the previous talk that, uh, fever is increasing metabolism and also brain metabolism means more profusion, means the risk of high ICP means also the risk of uh brain. Eema. And also one part is hemodynamic instability. And, uh, from the patient care, um, and the, the observation, it's very nice to see if you have a patient with high grade fever and you see a hemodynamic instability, you control fever to normalthermia, and then you, you see that you have much more, uh, you're much more stabilizing, uh, the patient. And one, also important, uh, point that I would like to emphasize here is that, um, Uh, temperatures also associated with, uh, spreading depolarizations and, uh, spreading depolarizations are to my mind, one of the newer, very old, known, we know that, uh, since many, many years, but now they are introduced in order to care again. Because we know that these cortical spreading depolarizations, they occur, especially when the brain is exposed to ischemia or exposed to blood. And these are the diseases we are talking about, and these cortexpecting depolarizations can uh Unfortunately, not be monitored non-invasively. Only invasive methods, um, can capture these, uh, phenomenon, but we know that these phenomena are very energy consuming and it's, it's like 8 times energy consuming compared to a seizure. And in these two publications, the left is on TBI patients, the right is on patients with intrace hemorrhage. You see the association of um the incidence of, uh uh spreading depolarizations, the probability of spreading depolarizations uh associated with higher temperature. Again, no causality, but, uh, there is a strong, uh, association. We know that these spreading liberalizations, when they occur, they can occur in, in so-called clusters. So they, they repeatedly go over the brain, the, the gyrus, and on the right side, on the lower part, you see a patients with sparate hemorrhage, where we don't, uh, with, without having any vasospasm, that's important and, uh, with these rim enhancing lesions on the, on the cortex, and most likely this phenomenon of the secondary pathology, a corticostatic debrizations. And we don't have a, uh, a good control of these spreading liberalizations, and it's important to know that these are also neuroprotective. So you have to identify the, the patients with clusters, of course, with spreading liberalizations and maybe then treat and there's uh a study ongoing on, on ketamine, um, and, uh, temperature control is an, is an observation from case report, uh, case reports that, uh, that might also be an option um for the treatment. So if we now consider what is targeted temperature management, um, is the role still of hypothermia? Um, I start with uh ischemic stroke. We do have several studies which were, uh, unfortunately not, uh, finalized and the, the recruitment was, was very low, uh, in, uh, uh, patients with this ischemic stroke and one Uh, message, what we really learned that, uh, is that, um, cooling awake patients is very difficult, uh, because you, you always enter into, into a secondary effects like, uh, like shivering, and that's why, uh, the question of the feasibility in awake patients of hypothermia, and that's what we learned, I think very much from, from the strokes, uh, studies. We see that the targeted temperature of 33 or 34 to 35 degrees within a very short time, which is important in stroke patients. But we don't have an uh association with improved outcomes. There was a high risk for, for higher rate of pneumonia. And, uh, so we don't have a clear message in, in, uh, stroke patients because after these studies and they were not finished because of uh low recruitment, um, no, uh large randomized trial was, uh, performed. In subreinate hemorrhage, we don't have a randomized control trial. There's, there, there, there's some single center or so um uh more centers involved in the question of the treatment of refractory vaso spasm, for example, with, uh, showing arsenized results then that the, the DCI was decreased, but this is observational and, and not a randomized controlled trial. Intracebral hemorrhages, uh, to my mind, uh, quite interesting, but again, we don't have large trials and uh the, these trials were either not, not finished or the change trial with a very low number of patients. Uh, which, uh, were all patients were, which were mechanically ventilated. And, uh, I think what Andrea also pointed out at the beginning that, uh, there is an interesting effect on the reduction of edema and that's why, um, I, just from the better physiological point of view, I, I point towards uh this small, I, I would say case series. It's not, it's not a rare study. Um, hypothermia, you see, in, uh, uh, you see the intraceal hemorrhage, so whitish, and then in, in bluish around the edema, and then the upper level, you see in, uh, a patient with ineral hemorrhage, uh, evolving with a large midline shift, increasing edema in the control group and in the hypothermia group. Um, you don't even, um, if the patient had an EVD, uh, at the 11, you don't see the increase in edema. And the graph on the right side is quite interesting. So the, the dark light, uh, the dark, uh, trace shows that, um, this is the, the, the group with edema development and you see the rising, um, a slow. Here with the group who the control group, so no hypothermia and the increased volume of edema compared to the control group. And so hypothermia had an effect on, on the development of, uh, of edema. And it's important to know that the intervention was stopped, uh, day 7 to 10, and there was a long-lasting effect even afterwards on, uh, brain edema. So if we consider that, you, you obviously ask when is the maximum of edema and when, uh, when should you start with the intervention. And there's also some retrospective, observational, but nice thoughts that, um, if you start the intervention, you, you should start it early. And I think that's uh a message we have an intraceal hemorrhage and blood pressure control, or reduction of blood pressure, uh, is the target. We have to be, uh, aggressively reach our target, uh, very early. Uh, despite we know that, uh, edema develops over time and the maximum of edema is usually reached at, uh, at the end of, um, week 2, to be honest. So it's, it's around day 10 or even, uh, day 14. So we don't have a good evidence for hypo to support hypothermia and ischemic stroke and suffering hemorrhage. And also in intracellular hemorrhage. So what about nomothermia and uh fever? Um, I think if we discuss about fever, it's important to consider what is the definition of of fever and even if you ask experts, uh, if you ask clinicians who daily treat patients, Everyone has a uh a different definition of fever. And why is that important? Because usually fever is the trigger for an intervention. And you see, the majority says that fever is around 38 degrees or 38.3 degrees, and that's mostly the time when uh physicians start, uh, treating fever or in acute brain injured patients. Um, temperature depends on the, on the measurement method, and it's clear, if you wanna control temperature, you have to measure it continuously. The, I, I think for all the patients we have, for all the critical patients who are mechanically ventilated, we should monitor continuously, uh, temperature. And obviously, it's not the skin temperature, it's not the tympanic, uh, uh, temperature. You need a central temperature, uh, measurement like the esophagus or, uh, the bladder. The question is, is the brain temperature different? And the answer is very clear, yes, the brain temperature is different. Does it matter? We don't know. And, um, obviously, if you, um, ask yourself what is the best, best methods to measure brain temperature, it's very difficult to measure, uh, brain temperature noninvasively. If you do that with imaging methods, you have an estimation of brain temperature. And what you realize that temperature is also focal regulated. So if you measure, uh, around the lesion, it's totally different, uh, from the healthy appearing brain tissue. So should we measure brain temperature, um, to my mind, uh, yes, because, uh, for me it's an, it's an important additive information, but, um, and non-invasive measurement is for now not, uh, reliable. Um, if we now come to the treatment part, uh, the, there are different ways how to treat, um, patients with acute brain injury, obviously pharmacological agents and the physical methods, and the bottom line is, um, that pharmacological agents are, uh, OK for fever control, so you decrease temperature, but not to the extent of nomothermia of sustained nomothermia or of a hypothermia. This is, this is, uh, a mission impossible with, uh, pharmacological agents, hypothermia, which, uh, will not be reached with that. Physical methods, um, are very effective, especially if you have uh feedback devices, controlled feedback devices. And that's, that's like blood pressure uh control, you can control temperature easily to a certain target, which could be normalthermia, hypothermia, um, and, uh, obviously also target a certain temperature above 37 degrees if that is, uh, what you want. The, um, this is a study we published several years ago where we looked at, um, uh, different effects of medication on temperature and you see on the graph that we also started the, um, uh, giving antipyretics, uh, around 38.5 degrees at that time. So 38.3 was actually The, the, um, the level where the nurses were introduced in increasingly you see that the mean was uh about 38.5 degrees. You see the decrease of temperature afterwards in the hours afterwards with a maximum of uh 3 or 4 hours, and then, um, obviously, the temperature is increasing again. And what we learned from that study, this is not a comparative study. This is an observational uh uh study of prospectively recorded, uh, data of paracetamol, diclofenac and methimazole. Um, and what we realized is that, is that sustained normalthermia cannot be reached by, uh, these Inventions so by medication. I think that's, that's very important. So if we, if we talk about, you have a patients with fever, you start with the drug, and obviously everyone leaves, leaves the room afterwards and say temperatures gone, but it's gonna, gonna reappear afterwards and you will never reach, uh, 37 degrees, um, in a sustained matter if that is your target. Uh, this is a meta-analysis and you, you might have heard, uh, or got it presented by Fabita Konner because this is, uh, in, in the last, uh, presentation, in the last webinar, uh, because this is on cardiac arrest and it shows that, that, uh, feedback devices are very efficient in, uh, controlling temperature and also, um, in, uh, um, in terms of outcome, uh, after cardiac arrest, but this is, as I said, not the topic here. And if you think About how to control temperature. I think you have to make it properly. And if we, uh, look at many, many studies, including, uh, the TTM2 trial, we see the large variability of, of the temperature and the intervention group. Um, and there are some studies with feedback devices which show that the variability is not very high. And I, I think for, for me, the message is, if your target is really controlling temperature, you have to use an appropriate method, um, to do that. So what do the guidelines tell us, the guidelines um on uh ischemic stroke, um, these are quite old guidelines, uh, 2015 specifically on TTM. And what the guidelines say in acute ischemic stroke and nomothermia, um, there's no routine prevention of hypothermia or prophylactic nomothermia is, uh, so, uh, is, is not, uh, recommended from the guidelines in patients with acute ischemic stroke and type. Hypothermia, there, um, there is no recommendation, uh, for treating hypothermia in terms of improving outcome or survival, but I also discussed about the better physiology, uh, what, what we think the temperature can, can make on the cellular level. And the third recommendation, um, is that induction of hypothermia, uh, prophylactic hypothermia is not the way to go in ischemic stroke patients. What about intracellular hemorrhage patients, guidelines, especially of the American Heart Associations are, um, published in 2022. And if you, if you look here, the recommendation is that in patients with a pharmacologically treated, uh, treating uh elevated temperature may be reasonable to improve functional outcomes. So there is an idea of pharmacological treatment. Uh, in patients with spontaneous ICH, it's a usefulness of therapeutic hypothermia, uh, is unclear because we don't have, uh, large trials, um, on that question. What about suffage hemorrhage? Um, the AGA guidelines, uh, changed a bit. The last guidelines in 2012 uh said no thermia is reasonable and the more recent guidelines, um, stated in SAH patient, the effectiveness of therapeutic temperature management is in the acute phase of SAH is uncertain. Interestingly, in the very recently published guidelines in care of SAH uh temperature is not managed, uh, is not mentioned and also fever is not mentioned, but I think, uh, that's, that's quite, uh, uh, um, it, it's not appropriate that the picture was not, uh, part of, uh, these guidelines. So what about trials? Um, trials on normalthermia. This is, um, a trial we conducted in, in Austria several years ago and I, I, I can, uh, very good remember, very well remember, uh, the time when we included these patients with, uh, uh, intracellular hemorrhage, um, ischemic, uh, stroke, and you see that appropriate patients were selected in the ICU. So NA. more, more than 14, for example, or poor grade uh SIH patients, and they were um uh nomothermia was the target for 37 degrees, was the, the target for 7 days in ischemic stroke and hemorrhagic stroke, um, and for suffparation hemorrhage, uh, even for 14 days. What have we found is, it's uh feasible. There was no difference in mortality, but the study was not uh power for mortality. And the fever burden significantly decreased from 9 hours to 1.5 hours. And another effect which was nicely seen that, that the burden of work for, for nurses was actually less in um the feedback devices. And then very recently, we published um the uh um the Intrepid study Impact of Fever Prevention in being injured patients. This is a randomized, uh, controlled trial in ischemic stroke, contraal hemorrhage, and SAH patient. The intervention was by temperature management versus uh standard care. And the primary outcome measures, uh, was, uh, fever burden, um, uh, very important secondary outcome measures, clinical endpoints, um, and, uh, the important secondary outcome measure, the principal secondary outcome measure was 3 months to modified ranking scale in a shift analysis, um, for, uh, where the, the trial was powered for and that's, that's very important. Fever burden, um, fever burden was, uh, calculated, calculated by the daily mean, so the daily mean fever burden was calculated for every patient and, uh, that's the area under the curve of the temperature above 37.9 degrees divided by the total number of hours in the acute phase multiplied by 24 hours. That we, that's why you got for the fever burden at 0 2.7. Um, result which you will see in the next slide. So this study was undertaking in uh US altogether 43 uh uh sites also in Switzerland, United Kingdom, the Netherlands, Germany, Austria, and also from uh South Korea. It started in 2017 with the, uh, last patient being included in 2021. This is, these are the number of patients included. It's important to know that there was a pre-planned interim analysis, um, after 588 patients, and after that interim analysis, the study was stopped, uh, because the secondary endpoint, uh, where the study was powered for, uh, was. Not reached in terms of the modified ranking scale. Uh, I will come to that later on before I would, um, emphasize the patients, uh, they, they are widespread in terms of the inal hemorrhage, SIH and ischemic strokes, or more than 200 patients. I think that's a very important study because it's the largest study, the largest prospective study on, uh, temperature control. It's also important to know that, um, the patients, uh, were stratified according to the severity, just of the hemorrhage. High grade with an ICH score of 3 or more. There was uh slightly less patients, but a comparative uh patient number would be of SIH patients and ischemic stroke patients stratified as severe SIH or ischemic stroke and uh moderate to mild uh ischemic stroke. This is the uh primary endpoint of the, uh, average hourly fever burden, and you see that the treatment was, uh, effective, so fever prevention was very effective, effectively performed by the intervention group and you see that, um, the fever prevention led to a significant Uh, reduction of hours of fever in the intervention group that was 9 hours median compared to 2021.6 hours in the standard care group. And this um result was the same in the ischemic stroke, intercellable hemorrhage, and a rational hemorrhage, but there was no difference in the secondary outcome which that was powered originally powered for in uh uh Moran score, um, the shift analysis. And also the patients with a modified ran score from 0 to 3. Um, it's important to mention the adverse effects. There was no, no significance in the adverse effects in terms of pneumonia. Um, if you look at the pneumonia rate, the lamonia rate was 1/3, around 1/3 in, uh, both cohorts. Um, which is obviously, um, uh, could, could be interpreted as high, but, uh, it's important to know that there was no significant, uh, difference between, um, these groups. Shiring, uh, was much higher in the intervention group, and this is important, uh, to know, but, uh, this continuation of the treatment, um, was, did not, did not happen, uh, only happened in 70, in 7%. Um, of the patients due to shivering, means that the centers who, uh, participated were well uh aware and established a good shivering protocol, uh, shivering prevention and shivering treatment protocol so that discontinuation of the, the device, um, was only performed in 7% of patients. Now, the question is what, uh, are the next step and how, how should we interpret that. I think it's important to mention that, uh, in both, uh, groups and intervention was performed, uh, pharmacological intervention and, um, the device intervention in the, uh, in the other group. And, uh, it's important to recognize also that 25%, uh, in the, in the control group never developed a fever and we don't know how, how many that, uh, were actually in the intervention group. So what are uh the answers, is there a simple way to go or is it, is it more complex? Um, and I think it's, it's complex. Uh, I think for also the communication and um the further, uh, design of the studies, we need clear definitions of nomothermia, hypothermia, uh, and fever, and this was well done by the, by, uh, in this, uh, publication. And for now, we are left with expert opinions, expert recommendations, and I just put the main expert recommendations here. Uh, temperature should be measured. I think that's a very important, uh, uh, message. If you don't, um, measure temperature continuously or at least hourly, you will not capture the events, uh, of fever. An automated device is indicated for high quality temperature control, and that's important. So if you, if you say that, uh, the temperature is a piece of your management strategies, um, then your goal is high quality control and you need an automated device because, uh, otherwise, you will not capture the episodes of fever and also the pharmacological interventions are not, not very effective. Um, TTM should be employed reactively, so we don't have, um, evidence for now that we, uh, go from a normalthermia in every patient proactively, prophylactively, and that's why in this experts recommendation, maintaining nothermia is, uh, the recommendation of, of experts, um, reactively, so meaning that, um, um, you wait until you see that the patient is really developing fever and then you start, uh, the intervention. What is the, uh, the target temperature, it's between 36 and 37.5 degrees. Also very important to keep, keep that, uh, range and the temperature control should be, uh, employed for as long as the, as the brain is at risk. And, um, that question is very difficult, how long that is I think. Uh, for SCH patients, it's, uh, for, for the prolonged period of vaso spasm. In ICH patients, uh, especially in severe ICH patients, we know that the edema is evolving over time and as I said that the maximum is at day, day 10 or maybe day 14. And, um, in acute ischemic stroke, also we know that edema development can occur uh days after. The, uh, um, there are also uh other expert recommendations which also recommend nomothermia in, uh, uh, he, hemorrhagic stroke patients, um, and also the, the British recommendation goes to the same, uh, direction. So in summary, I would like to say that, uh, following hemotic stroke or ischelic uh stroke, stroke patients who require critic care admission, very important. Uh, core temperature should be continuously monitored and target temperatures between 36 and 3 7.5 degrees. Um, for high quality control, you need feedback devices. TTM should be, um, uh, started, uh, within the first fever identification, and, and again, if you don't properly monitor your patients, you will not identify that. Uh, maintain, maintain as long as the brain is, uh, at risk. No prophylactic hypothermia and stroke patients, I think we need to study, um, especially, uh, looking for ICH patients because, uh, in edema development, I think there is, um, a lot to, to learn, uh, in the future. So having said that, I would like to uh thank you for your attention. Um, thanks for inviting me, and I hope that was very informative all of you and I will start with the discussion. Thank you much. Thank you, Raymond. Uh, so, I think, uh, both of your presentations have been uh amazing. Uh, thank you very much, uh, for, uh, this contribution. I think we have some time for questions. Uh, there are some questions in chat, and, uh, I encourage the audience to ask for even more questions. So, mm, I I would like to start with some, uh, clinical and pragmatic advices, uh, because I think that, uh, people who are listening to this, uh, uh, talk have understood what the guidelines say, uh, the, uh, what the science says, but then they should, uh, now go back to the unit and start to do, uh, what I called inappropriate and good TTM. So my question is, uh, where should people start from? For instance, the monitor. Uh, when you have a patient with acute brain injury, subarachnoidal hemorrhage, etc. do you always monitor the core temperature, where, for how long, uh, or you measure the external temperature every 8 hours? And which is your practice in this? I think that the question goes to me. Um, so we, we are very, very much, uh, used to the foley catheter. I, I know that this is, this is not, not common in every, um, uh, ICU and that's, that's why we don't, don't have major concerns of that. And then in, in patients who are anyway, um, uh, in, in the bed with the severe brain injury, we monitor continuously. Um, what we have recognized, um, also when, when we, um, uh, go, went back to our data, um, if you discontinuously measure the temperature, you, you will not capture these increases and that's why. Um, taking, uh, a gap of 6 or 8 hours in, uh, uh, mechanically ventilated patients is not justified and that's, that's why, uh, also in the recommendation, it's an hourly measurement in the critically ill patients is indicated. Thank you, Raymond. Uh, I will proceed with the question maybe for Andrea. It's a can I, can I make a comment on that, that previous question as well? We also, as Professor Alb have, uh, um, it is, it is part of our standard practice to monitor, uh, temperature continuously. Another aspect that's quite important, I think, moving forward is that We have some insight emerging from uh uh patients, uh, this is mostly in the traumatic brain injury patient population when you have uh invasive brain physiology monitoring and you get brain temperature as well as core temperature, is that even within core temperature sources, you can have significant gradients. So you might have, uh, esophageal or bladder temperature that are quite different from brain temperature. And if it, if it's, uh, there are Two aspects of it. So, definitely, uh, as a basic approach to, to monitor, core temperature continuously. But also perhaps there might be a role to clarify whether we should target brain temperature because that's our target organ, or whether core temperature is good enough. And this is what we need to answer in the coming years and months. Thank you, Andrea. This is, uh, I think, a very important point. I, now I would like to challenge you a bit with uh a, a tricky question. So, we discussed about the trigger. OK, trigger when to start to treat uh fever. Now we have understood that must be at least poor temperature. That's fine. My question is, uh, uh, do you also look at the trend and decide on the basis of the trend when to start fever treatment? I mean, I'm imagining a patient where you are. Over the hours, a progressive, quite quick increase of the temperature. It doesn't arrive yet, probably maybe at the trigger of what we call fever, but would you be more aggressive in these cases to avoid, to arrive and have problems in managing it? That's a great question. The, the, the, the pragmatic angle is that when a patient is developing fever, uh, what you observe is an increased variability in their temperature. So typically they will mount a fever. I think we're pretty good, uh, uh, at giving, um, paracetamol in our case, occasionally diclofen when temperature exceeds 37. 0.56 by the time the nurse gets it, it, uh, temperature is often in the 38. And then you have, as a professor Professor Albo has shown a decrease in temperature and then you see another little mount. And because we capture uh this information digitally, you see this rocky uh uh pattern, uh, by which I think by the time we are administering the second dose. Of paracetamol, we have uh uh established some automated uh temperature management device. So I think um if I can add on that, so stability of temperature is important. Um, if you, if you just, uh, think you, you're a neuron and, and you're exposed to the variability of whatever block pressure or temperature, I think that matters. Um, and that's why, um, this variability and there's some studies as in all the diseases that show the variability is, is associated with, with worse outcome. The, the other question you had, um, in terms of the trend. I think that's, that's very, very, very difficult to answer. I think if, if the patient is critically ill, I'm more aggressive in, in the fever treatment. And I, if I have an ICB monitor and, and, and see that the patient is on the edge of developing a high ICB then I'm more aggressive in, in doing that. And I think that's, so seeing the surrounding and, and, and other organ systems in the connection with temperature is important and, and drives me to be, to be more aggressive. But uh in, in some patients, we know that temperature control is so difficult, and then we, we, we start. Temperature to normalthermia. Nothermia is the, the most difficult, uh, goal to reach and the patient is starting shivering, and then, then you, you do the heck of everything against shivering, and, uh, that's, that you, you're gonna run into a very, very difficult, uh, situation afterwards. So, look at the patient and that, uh, I think, um, temperature, as I said at the beginning is a piece, but it's an important piece in our critically ill patients. Thank you. Thank you very much. We have a question from uh uh uh someone from Philippines, so very far away. Uh, the, the question is, do we still follow the 1224 hours duration of TTM or it depends? And if I can add, I think Raymond was mentioning that the temperature control should be done as long as the brain is at risk, as the guidelines say. It's very difficult to define when the brain is not at risk anymore. Could you please help to clarify about this point? I think the, the question more relates to cardiac arrest patients 12 hours or 24 hours. I don't, I'm because the, the, the, the idea in SAH patients are in hemorrhage or uh 2 patients was never 12 hours. Uh, it was, it was at least 3 days or, or even, even longer. Um, and, uh, that, that question is, is also difficult to answer, uh, in, in, we know that racial spasm is in this situation, for example, is not happening, not highly likely at the at the subacute. Uh, but it happens in the 5678, and so I think that, that's the critical phase in as AIDS patients and then in the very early, uh, stage when a brain injury occurs, that's also a very critical phase. In in hemorrhage patients, um, if our aim is to decrease the edema, I think we, we need a study to answer the question. Uh, but, uh, this pre preliminary data shows that you, you have to, to sustain, uh, the intervention quite long. Um, but again, it's a combination of, of the imaging of the patient and, um, of the clinical condition, but Uh, I also would like to emphasize, um, I, if, if I think the patient should wake up, the patient should wake up. I do not prolong, um, any intervention, uh, just for the sake of the intervention. Um, and that's, uh, I think, an important point we should discuss here about how aggressive and how long we should sustain certain measures in the military. Thank you, Andrea. Any thoughts on this? Uh, I think Raymond raised uh a lot of points, uh, very early. and I agree, uh, on the whole life, uh, on the whole line. The, in terms of how long we, we prolong, uh, uh, uh, temperature control and how do we define when a brain is at risk. We have to rely on the information we have from imaging, perfusion scans, and multimodality mon monitoring if that is available. And it's, it's very much, uh, a judgment you have to make. When treating each individual patient. And in terms, uh, uh, of temperature control, specifically, Professor Elber raised the key point, which is if you're cooling the, the whole body, shivering, uh, will fight that very aggressively. And so, do you sedate and paralyze the patient so that you can control temperature better. Probably not, unless in very selected cases, if you have a scan which shows impending herniation, but you wouldn't, you wouldn't be waking that patient up anyway because you would provide sedation and ventilation to control CO2 so that they know, they, they don't have Uh, a herniation in those patients, you would of course uh uh uh control temperature as well. The more difficult case, uh, and one perhaps we should, we should focus our research efforts is about the patient that has, uh, uh, um, suffered an aneurysmal bleed and is in that window of, uh, between typically day 3 to, week 3, but most typically around 7 days after bleed when they have maximum vasospasm and a great area of brain at risk. And for whatever reason, they, they do not tolerate map augmentation. And you see that there is brain uh at risk clearly on a perfusion scan. Um, do you try and control temperature or are there other options such as only cooling the brain or, or, or, or the blood flow to the brain? Just something we are looking at. But, uh, there are more research questions than practical answers. Thank you. Thank you very much. I think that, uh, uh, we are running out of, uh, time, and I'm sorry because I would have, uh, even more and more questions for you. I think that, uh, this webinar has been very useful for the audience, for me as well. I have learned a lot. Thank you very much. Uh, I would like to remind you that, uh, in a few months, there will be the 3rd part of, of, uh, the webinars related to temperature control. And in this case, uh, the topic will be traumatic brain injury. But for now, please let me thank again SICM and BD for the great organization and for managing this webinar. And a big thanks also to the two speakers of today, Andrea and Raymond, and thank you to all of you who have listened. Have a great afternoon. Thank you very much. Thanks. Thank you. Created by
