SCCM Resource Library-Targeted Temperature Management after Cardiac Arrest

Video Transcription

Welcome, everyone, to today's webinar. Our title today is Targeted Temperature Managements. The purpose of this is to bring in a live discussion and lively discussion regarding  a recent study that was published just a few months ago, Targeted Temperature Management number two. My name is George Lopez. I am a neurologist. I'm a vascular neurologist,  a neurointensivist. I've been practicing clinical medicine and also as a clinical trialist and have examined numerous neuroprotectants over the decades. And I'm excited to be with  you and have you guys join us today. We've got close to 500 participants today. So welcome,  everyone, from all over the country and probably also internationally, too. So welcome again.  So this webinar is being sponsored by the neuroscience section of the Society for Clinical Care Medicine. So I am the current chair of the neuroscience section. And on behalf of  our section, welcome, all of you. So today's webcast is being recorded. So you can always  come back and share it with your colleagues. It's not available to view live today. Unfortunately,  there is no CEs available for today's presentation. At the end, we do have a chat box. So please  feel free to enter in your questions. I plan to have at least 15 minutes at the very end of this  webcast to address your questions by our panelists. So feel free to type them in. Probably we'll not  get to the questions during the initial introduction and background material review.  So let me start. Here's some nice disclaimers for everyone. Educational purposes only. And the views  and opinions expressed are those of the presenters and not necessarily reflect the opinions or views  of the Society for Clinical Care Medicine. So let me start by introducing our two esteemed  speakers in alphabetical order. So first is Romer Geokadin, who is a professor of neurology, anesthesiology, critical care medicine, neurosurgery, internal medicine at Johns  Hopkins University. He's been studying acute brain injuries now for several decades, both in the laboratory and also at the bedside. He works as a bedside neurointensivist. He is  one of the recent past presidents of the Neurocritical Care Society. And his interest in hypothermia is, an example is his ongoing current recent trial called IceCap. And we'll  get to his background discussion of that trial and tell us a little bit about how that trial  is going and the background of that. And he has no commercial or industry disclosures to disclose.  And our second speaker and panelist is Dr. David Greer, who is the professor of neurology and the  chief of neurology at Boston Medical Center and is currently the chair of the Department of Neurology at the Boston University School of Medicine. He has multiple NIH grants and  research funding. He currently is running, conducting, and soon to complete a industry sponsored trial called the Intrepid Study, examining the role of temperature modulation  in various acute brain injuries. So what I'm going to do is give you about a 10-minute background  on cardiac arrest and temperature modulation. And then I will jump forward into the current  recent studies that brings us to the most recent study called TTM2. So those of you on the webinar  certainly know what this represents. So this is a ECG. And to me as a neurologist, this shows  cerebral standstill. So this is a large acute brain injury to a practicing neurologist. So we  don't need a CT or MRI to know that this patient has suffered a severe brain injury. Next slide.  So just to put this problem into perspective, this is certainly not just a problem in the United  States. This is a worldwide problem. There are over 3 million cases of sudden cardiac death  worldwide. Here in the US, there's at least 367,000 patients that die from a cardiac cause,  known as sudden cardiac death. And a vast majority of those patients, I should say only a few percent,  approximately 10% actually survive their sudden cardiac death. And of those survivors, only a fraction of those, probably less than 10%, actually have a good neurological outcome.  So it's a fairly devastating acute brain injury. Next slide.  So these next few slides were kind of gifted to me from Kees Polderman, who has also studied  hypothermia and acute brain injury over the decades. This is from a 12-year-old review article that was published in Critical Care Medicine, where he kind of describes some of  the cellular and molecular mechanisms that go into play after an acute brain injury. And it's  not just cardiac arrest, but other types of acute brain injuries. And what we'll see in the next slide is that a lot of these processes are all temperature dependent. Next slide.  And these are all stimulated by fever and most interestingly on the next slide these are all modulated by hypothermia.  Next slide. So having practiced in the Neurocritical Care Unit for numerous years,  next slide, I jokingly consider it a hyperthermia unit. And it's not just the Neurocritical Care  Unit. So any of your ICUs that you practice in, be it the surgical ICU, the medical ICU,  et cetera, fevers are very, very common. In fact, they're very rampant, especially in those  patients with an acute brain injury. And that's kind of where we hope to see where neuroprotectants  might be useful. And hyperthermia has been one of the ones that has been studied probably  the most over decades of both laboratory and clinical experimentation. Next slide.  So I can't give a presentation on hyperthermia and acute brain injury without showing this slide, which shows a picture of Dr. Peter Safar, who was one of the founding pillars  in critical care medicine. In fact, he established probably the first intensive care physician-led  intensive care unit in the United States in Baltimore back in the 60s. He spent his entire  professional life and career studying resuscitation, is one of the founders of resuscitation  research, and looked at and examined the role of hyperthermia. And in this cartoon from one of his  papers in 1964, and he also helped develop along with others, the ABCs of resuscitation. But if you look down at the bottom, he talks about recovery of the acutely injured brain  after cardiac arrest, and has hyperthermia as one of the items to address in the recovery. And he  says, start within 30 minutes of no sign of CNS recovery. So amazing insights into the CNS injury dating back decades and decades. So let's fast forward. Next slide.  Lots of research, both basic and clinical research in the use of hyperthermia. Next slide. And that's where two kind of landmark studies, both published in 2002,  in the same issue of the New England Journal of Medicine, one coming out of Australia, the other coming from our European colleagues, and I'm sure everyone is quite familiar with  these two landmark studies. This really set off a lot of the ongoing clinical studies in evaluation of hypothermia as a neuroprotectant. Next slide.  So I'm going to start with the Australian experience, quickly review. These were studies randomizing patients who were comatose survivors after a cardiac arrest,  that had an initial rhythm of ventricular fibrillation, they were comatose. And in this study, they actually started cooling out in the field. And the next slide, you'll see  how they actually cooled patients. And this is from their article. Next slide.  And they use ice. As you can see, a lot of the ice is centered around the head of this patient.  So this was not a study using more modern day technologies that we have available to induce hypothermia. So keep that in mind when we look at the numbers on the next slide,  and at the outcomes, both mortality and neurological outcomes. So they targeted 37 for the neuromalthermia patients, and then they had a target temperature of 33 degrees.  It was a small, relatively small study by today's standards.  43 patients randomized to hypothermia, and 34 to neuromalthermia, they cooled them for 12 hours.  Next slide. And even with those small numbers, and even with that technology of using ice packs,  they had a much improved outcome in terms of, quote, good outcomes in the patients that  underwent hypothermia compared to those patients that did not undergo hypothermia, their control  group. Mortality, although there was a trend towards improvement in mortality, it did not  reach statistical significance. You may ponder it may have been because of the small numbers or other reasons. Next slide. So that was the Australian group. The European experience,  they had a much larger number of patients, still relatively small compared to today's clinical trials, 137 patients assigned to hypothermia, and 138 patients assigned to their,  quote, neuromalthermia group. And these patients either had a ventricular fibrillation as their  cardiac rhythm or non-pulseless VTAC. Next slide. Again, cooling to anywhere between 32 and 34  degrees, they used a water-cooled mattress and air-cooled tent that completely surrounded the  patient. And they cooled the patient for 24 hours, and then followed by active rewarming thereafter.  Next slide. And the Europeans, possibly because they had a larger number of patients,  they were able to show a mortality benefit in those patients that underwent hypothermia treatment  from 32 to 34 degrees versus those patients that were not cooled. And they did have a higher  proportion of patients that had a more favorable outcome in those patients that were cooled. Next slide. So fast forward multiple years, numerous clinical studies,  single-center experience, utilizing targeted temperature management, induction of hypothermia.  And finally, it became, hypothermia and early post-resuscitation care became part of the chain  of survival in our cardiac arrest and our ACLS algorithms. Next slide. So it became almost,  almost standard of care in most institutions. Next slide. However, then came another study.  This much, much larger study. This came from Nicholas Nielsen, European group of clinical  trialists. Next slide. Which randomized patients to either 33 degrees or one can consider 36 degrees  as still targeted temperature management and mild hypothermia. This was published in 2013,  much larger patient population, 950 patients were resuscitated from out-of-hospital cardiac  arrest and randomized. Next slide. And I think everyone on this webinar knows the results of this landmark study, which I'll call TTM-1 in comparison to the upcoming TTM-2 trial.  And unfortunately, there was no real statistically significant difference in the immortality of patients that underwent 33 degrees versus those patients that were cooled  to 36 degrees. And if you look on the left, the neurologic outcomes using the cerebral performance  scale or the modified Rankin, really no statistically significant difference between the two groups. Next slide. Next slide. So from that trial in 2013, numerous,  numerous publications, too many to count, described experiences in how centers, how intensive care units changed or did not change their approach to the management of  cardiac arrest, comatose cardiac arrest survivors. This was published in Critical Care Medicine and not to belabor it. Next slide, please.  Came the topic of this webinar, which is now TTM-2. And next slide. So again,  a huge study, and this also led by Nicholas Nielsen. Their objective was to analyze both  the beneficial and also harmful effects of targeted temperature management, namely 33 degrees  versus maintaining normal thermia, which was defined as 37.5 degrees in patients who survive  out of hospital cardiac arrest from presumed cardiac or, as we'll get to, an unknown source  of their cardiac arrest. Next slide. So their trial design, multi-center,  this was mainly conducted in Europe at 65 hospitals in the European theater. Australia also participated. In North America, there was only one site in North America. So when we talk  about generalizability, this needs to be considered. These were adult patients that were survivors of out-of-hospital cardiac arrest. Next slide. And another point is this was a  superiority study. Their outcomes, their primary outcome was mortality at 180 days, and their  secondary outcomes is neurological functional outcomes utilizing either the modified Rankin score or various health-related quality of life scores, and also looking at pre-specified  adverse events. Next slide. So if you remember the mortality graph from TTM1, this is very,  very similar to that. This is the mortality graph looking at mortality from days of randomization  into the trial between the normal thermia group versus those patients that underwent  hypothermia to 33 degrees. Again, a very large patient population. Next slide.  So their primary outcome, obviously mortality, secondary outcomes, as I already mentioned. Next slide. And so that is a long background, but I wanted to make sure that everyone's on  the same page and kind of understands the challenges of this challenging clinical  problem of cardiac arrest and acute brain injury. So my two panelists, I'd like to begin a  conversation and discussion of these studies, and more specifically, the most recent TTM trial,  TTM number two, that was just published, and really dissect a little bit on this trial.  And then hopefully they will share kind of their experiences in their ongoing clinical trials and  what the future holds for us. And then at the end of this discussion, I want you, the participants,  to have some takeaway messages about whether or not and how should we change our clinical approach to these patients who are comatose after cardiac arrest. So I'd like to kind of  start out with looking at, as we do with any clinical trial, looking at the strengths and weaknesses of the study. So the first question to my panelists is, what are the strengths  of the current TTM2 trial? Now, certainly it was a large patient population, but I wanted to kind  of go through first the strengths and what you see as their positives. So I'll start with you,  Romer, and then we'll jump to you, David. Can you hear me? Yes. Thank you so much, George, for that review. You made our life a little easy by doing that. So the strength of TTM2  is that it showed us one thing, that this kind of a study in this magnitude could actually be  accomplished. And that is something that we need to learn from the Europeans here in North America.  And by saying that, I want to acknowledge the TTM investigators, because when we were designing  iSCAP, they were very helpful, especially Hans Freiberg. But I think the key point really is  the study was done well. I could nitpick on a few things, which I will, but overall it is very good. And so my only issue is people should stop saying that this is an equivalent,  that the findings are equivalent, because this is not an equivalency study. It's a superiority study that failed to show one as superior to the other. That's it. It's  a failed superiority study. Let's leave it at that. Let's not claim equivalence, because if this  was an equivalent study, they will need sample size that is way bigger than this. Number one.  Number two, I think, and David and I agreed with this because this is the other thing that we share  in agreement, is this whole issue of controlling withdrawal of life support and end of life, which is amazing how they did this. And I'm hoping we could do this in North America.  So I will leave there. But overall, I think it's good that they were able to do this and execute it at the tail end of the pandemic. Well, rather at the start,  the tail end of the study at the start of the pandemic.  David, would you like to share kind of your thoughts on kind of the strengths over and above  what PROMER has listed? Yeah, I would agree with my esteemed colleague, Dr. Jukayden, that it was  a very well done study. And the Europeans have really figured out how to do this. We were commenting on this before getting live with everybody that they got this down. And it's  really a tremendous contribution to the science. So hats off to them. Not only do they have a huge  N for the study and reached their accrual goals, they did it faster than they thought they would,  which is pretty incredible. Some other strengths, I think, that haven't been brought up before is  that their loss to follow up rates are extremely low. Even for secondary endpoints, they were  close to 90% for getting the six months modified Rankin scale scores and the other quality of life  measures. So that's just extraordinarily good that you can get that kind of follow-up. I can only dream of getting that kind of follow-up for the most of the studies that I've done.  So I thought that that was really very good. Romer mentioned the fact that they had stopping rules  for withdrawal of life-sustaining therapy. They also, the person who was assessing that was  blinded. The treating physicians were not blinded to the allocation arm, the temperature, which is  understandable, but the neuroprognosticators were blinded, which is great. Now, I don't  necessarily agree with all of their bad prognosis, good prognosis rules, and that's fine. I think we  can agree to disagree with that. But most studies just don't have any rules for these things and  they're totally left to the whims of the treating clinicians. So I thought that was extraordinarily  rigorous that they did that. So those are just some of the points that I would make, that it was  a very well-conducted study with some rigorous methods that most of us can only dream of when we do trials like this. These are all great points and hopefully will be included in  upcoming studies because this is not the end-all be-all trial. What do you guys think in terms of  limitations? And I'll start with you, David. I think there's probably going to be more limitations  than there are strengths, but curious to kind of hear what you thought are some of the major  limitations. And yeah, I'll prompt you for a couple, but I'm sure you'll hit all the ones. But let me first start with whether or not shockable versus non-shockable. And if you look  at the data, I mean, this is a potentially very heterogeneous patient population. Lots of different  things will cause a cardiac arrest. And especially nowadays with the opioid epidemic, we've got  patients coming in in PEA arrest, arrest from severe hypoxia. Certainly we've experienced  taking care of patients who overdosed, et cetera, et cetera, or even had surgeries in the hospital  and had an in-hospital cardiac arrest. So can you start by talking about  shockable versus non-shockable rhythms and whether or not we should be picking more of a homogeneous patient population as opposed to more of a heterogeneous patient population?  Well, I think that would have been a mistake to be honest with you. And I think that you  could criticize the trial in either direction. If they hadn't included them, they would have said,  well, you don't know anything about the non-shockable rhythms. And Hyperion had come out a few years before this that suggested no mortality benefit, but if you did survive  and you were cool to 33, you did better than if you were at 37 or whatever the control group  really ended up being, which we can get into a little later. So there was data that had come out  in the interim of over 500 patients from Hyperion. They had almost 500 patients in this study that  had non-shockable rhythms also. I actually think that's a strength. And it was a pre-specified  subgroup that they looked at that also didn't show a benefit. Or I'm sorry, as Romer put it,  and he's correct, a superiority of one over the other. I think that's a very appropriate way to  put it. So I really don't see that as a limitation. I think some of the limitations of the study  are that some of the elements of standard care in the ICU, such as sedation, paralysis,  mechanical ventilation, they were all protocolized. And that could be good or that could be bad. It may not represent what actual clinical practice is more broadly. So that may have  hurt their generalization, but that's also a strength because you want the ICU care to be fairly homogeneous. You might just say, well, that's not how we do it in our unit. And so  then you do your own trial. Again, they couldn't blind the treating members of the team. That's  pretty much unavoidable in my opinion, but maybe not. There was no control group without any  temperature management. Both groups had temperature control. And there was crossover to a degree,  sorry for the pun. But the one that was assigned to normothermia, 46% still ended up on a temperature  control device. So we don't know, and we'll get into this a little bit later on, whether not  treating fever at all makes a difference. And I think that that needs to be studied. I don't  think that that's a good assumption to say it doesn't matter what you do with the temperature.  I think it does still matter what you do with the temperature until we figure that out. I'm sure that's a relief to a lot of people on the call right now. And they didn't have any  in-hospital arrests in the study. I think that's a limitation also. And we do think that they  behave differently. And I guess they had to cut their losses, but that's a tough one. And although  they had stopping rules is the last thing I'll say. There's almost certainly going to be an  impact of withdrawal of life-sustaining therapy in any of these studies. And how big that impact  was and could it have affected one of the groups more than the other? Unclear. Hopefully not, but you never know. Okay, Romer.  My turn now. So, I don't even know where to start. But let me start by saying the key points  of TTM-2 study. The key point is that TTM-2, this trial did not show any superiority of any treatment. It also did not prove that 33 did not work. Because when you actually look at  the benefits, and we'll go to that, it's about 50%, right? The current wild-type non-cooled  patients in the United States has a survival rate of 20%. So that alone is fantastic. I sat on the  ACLS committee for over a decade, and this was the big struggle with AHA, CPR, all of that. We're  stuck at about 15 to 20% survival rate. These studies are clocking 50%. So that's huge. And  to say that it doesn't work is totally wrong. So let me get into this shockable rhythm business.  So I think the important part is when you read, when we read a clinical trial, let us read it  based with the perspective of how does this apply to my patient. And we are in the United States.  If you're in Sweden, fine and dandy, right? This is a beautiful study if you're in Lund, right?  But if you're in Baltimore, or if you're in Seattle, or if you're in Boston, this study is not  practical. This is not applicable, right? In the United States, when your shockable rhythm is 20%  or less, then the study means nothing, right? And cardiac ideology here is even around that level,  because the biggest ideology of cardiac arrest in the 80s right now is, as you said, George,  opioid arrests. So it's respiratory arrests. And with COVID on top, so it's like three-folds of the arrests that we see are not cardiac, are not shockable. So at the end of the day,  we have to step back and say, this doesn't look like American patients. And we could keep going  on with the other things later on that you want to talk about. So I'll stop there for now.  So the other thing, and you bring up these excellent points, is comparing different patient populations, different countries throughout the world. We in the  United States, as everyone knows, we have different bystander CPR rates than European countries. And the European countries do a fantastic job of bystander CPR with 80%, sometimes,  depending on the country. If you have a cardiac arrest, that's where I want to have my cardiac  arrest, on vacation, because someone there knows how to do CPR. Here in the US, I think the numbers  are maybe 40% bystander CPR. So I think it's a much different patient population. So there have  been arguments that maybe it's a sicker or less sicker patient population, because they had early  resuscitation efforts. They had early bystander CPR. In France, for example, a lot of the paramedic units, physicians are on board. So you're getting physician-assisted  ACLS algorithm in the field soon after a witness cardiac arrest.  So George, I just want to say something very important, because I was in another talk some time ago, and we're not putting blame on the Europeans for having a very effective  resuscitation scheme. It's just that we need to improve here in America. But from a trial  and a patient selection perspective, when you're in the ED deciding what to do, this is the thing  that should pop up in your head very quickly. And we will talk later, if we have time, about  what does this actually mean for brain injury? I would chime in, though, to say you may be right,  but you may not be right. And until we do the trial in the U.S., we actually don't know if 33  is superior to 37 or 36. So I don't think that we can make the assumption that it is better,  and it might be worse. So I just want to give that word of caution that not worse in terms of  causing harm, although we don't know that either. But it might be a safety issue, because there was a signal for actually statistical significance in this trial  that it caused more hemodynamic instability with the lower temperature. So we have to take that into account, that it is harder, and it is deeper, and colder is not always better.  Right. So I love Dave, but I have to respond very quickly about that arrhythmia, because if indeed  that arrhythmia is real, you have to expect that 70 to 80 percent, maybe even 90 percent of people  will have an arrhythmia after CPR. If that signal was indeed real, why is the outcomes and the  survival exactly alike? So yeah, I mean, the proof is in the pudding. It's there. The outcomes  are identical. So whatever that signal means is there. And the corollary to that is there were  multiple trials that showed proof of concept that cooling actually may benefit the heart,  although the results were negative. But we know that it stabilizes cardiac membrane when you  cool them. But I'll stop there. And, George, I know you have a long list of things you want us  to talk about. I do. Thanks, Romer. And another, I think, important point is this whole  standardization, and I'll put that in quotes, of withdrawing life support, because a large percentage of these patients died because of withdrawal of life-sustaining therapies.  And so the questions are, you know, A, should it be protocolized, standardized, to the point where  we have a certain amount of time to wait? And we've learned over the years that the longer you  wait, patients can and still do wake up after prolonged ICU stays from their coma, from their  cardiac arrest. So how would we, in a sense, design a future trial? And we'll get to ISCAP in just a  sec. You know, how should we protocolize prognosticating? We've got biomarkers, we've got  neurophysiological testing, obviously our clinical neurological examination. How long should we wait?  So, Dave, you want to start with how long to wait? And I know you've got a case report that  you published of a woman in status myoclonus, et cetera, et cetera. But yeah, how long is long  enough? Yeah, I mean, it's a great question and one that's very near and dear to my heart. We  don't actually know. I think we know in some patients when it's like gratuitously obvious, the ones that wake up really early, the ones that have horrible neuroimaging,  florid changes, but there's a big group in the middle, right? And one of the things I like about this trial is in their prognostication protocol,  the very first thing was confounding factors such as severe metabolic derangement and lingering sedation have been ruled out, quote unquote.  How they did that, I don't know, but at least they accounted for it. At least they made it part of the protocol. And I think this is a huge step in the right direction.  Again, I don't agree with their stopping rules entirely. I like some of it. I just love the fact that they had them and that they were thoughtful about it  and realized that this could be something that impacted this study and any study. So I hope that, I can't remember if ISCAP is doing it to the same degree.  Maybe Romer can tell us about that, but I really applaud them for having something like that in there. Yeah, so Dave, yes, ISCAP is doing it.  And so this is probably one of the areas that Dave and I agree wholeheartedly because we were actually on the AHA panel that actually reported a scientific report  on what are the scientific basis for neurological prognostication that should be done. And so it's actually very interesting  because the worst thing that we could do to these patients is to predict, because the problem is when you're doing a clinical trial, right?  You should try to predict the intervention that is ongoing and not your own bias. And that is what happens when you prognosticate.  You're actually self-fulfilling that prognostication when you withdraw. And so when we look at this across the board, many trials out there have failed, especially in critical care.  And the one thing that sort of like jumps up is the withdrawal of life support is 20, 30, or 40%. When your withdrawal of life support  is several times higher than your treatment effect, the trial is doomed to fail. And so that is the advantage here. And the other thing that is very important is this.  And I agree with David, there's a lot of subjectivity to this. So this opens an entire discussion, which if I have time later, but I'll talk here right now, is together with iSCAP,  we actually have a corollary study that the NIH funded, which we call PreciseCAP, which actually applies precision medicine. What that is, is I, so when they approach us,  I said, no, we're not going to do another prognostication study. What we actually propose to the NIH is, can we create parameters that will guide us  to treatment responsiveness and titrate our interventions and make it even better? So that's PreciseCAP. And when we have time later, I'll talk about that.  Karen Hirsch is the PI for that together with Jonathan Elmer. But what we're trying to do is balance that,  it's not just about prognostication. It's also, do we have the ability to stratify and do we have the ability to actually detect  responsiveness to the intervention that we're giving, i.e., temperature intervention?  So I'd like to ask probably the toughest question, and that is, based on this latest study,  well done for all the pros and cons of what you laid out,  should this information change our clinical practice and how we care for these patients?  Should we no longer cool?  Should we no longer use our temperature-modulating devices,  of which there are several commercially available on the shelf and currently being used? Do we abandon temperature modulation? Do we abandon cooling patients?  So Dave, you can go ahead and start there.  Yeah, I think it's a very legitimate question. I don't think by any means we should abandon temperature control for these patients. I want to be very clear.  I don't, maybe we'll get future trials and we can talk about that later that will tell us whether any temperature control helps or not.  But for now, I wouldn't feel comfortable not controlling somebody's temperature and keeping them from at least being hyperthermic. And I think that the TTM2 study certainly helps us  to have justification to keep them at least from being febrile at this point. So we did change our protocol when this came out, though.  And I know that that may be controversial, and I think this is an area where Romer and I do differ, and that's fine. Still part friends at the end of the day.  But we did change our target temperature to 37 unless somebody came in colder than that, in which case we had them there and then gradually re-warmed them over time.  But really for 48 to 72 hours, we wanted to keep no fever from happening. So that's a great point, Dave. I mean, if you look at the data,  a percentage of patients actually after their arrest come in cold, relatively speaking.  They're 35, I think, 35 degrees Celsius. So are you recommending re-warming your post-resuscitated cardiac arrest patient with an acute brain injury to 37 and then keep them at 37?  Well, there's two points to make. One is that I think we certainly leave it to the discretion of the treating clinician if they wanted to keep them at the temperature  that they came in at. Consider where they arrest. If you arrest in a snowbank with your head sticking in the ice, that's great. If you arrest in Florida  and your arrival temperature is 33, you know what that means, right, George? You were dead for a long time. You were starting to become room temperature human.  And so that may not matter what you do with somebody like that. We don't know that, of course. But keep those two things in mind, where they arrest,  what the temperature is, the ambient temperature. That may make a very big difference in these patients. Who knows? Yeah. Is it my turn? Yes.  Absolutely, we should cool, right? So I think that the biggest thing that I would like to say here right now is 33 is probably your best fever control.  People don't think of it that way, but it is, right? But let me just take a step back here because I'm a translational scientist in the lab. It's actually very interesting  because there's a study published by Olay et al in intensive care medicine. And that is the group of Nicholas Nilsson and those guys.  And what they actually showed in about 181 studies that, and they use the STAIR criteria, which is really the stroke people trying to do clinical, trying to do animal studies  that mimic the clinical situations. They found a very stark evidence. So we're not litigating whether temperature is near protective because from the group that did TTM2,  they actually found key things that the key temperature in all of this study in the meta-analysis is that the most effective range is 39 to 34 degrees,  that it should be started within two hours, that it should be done for at least eight hours on the average. And almost consistently, the neurobehavior, histology,  and all of those things improved in animals. Now, moving forward, having said that, I think it is very important that it is easy for us to dismiss animal studies  and say, but they're just animals. But at the end, that we should remember that the clinical trials are really a poor representation of the idealized situation of animal studies.  And this is where, when they don't match, we blame the animal studies, and then we don't look at how faulty we're doing clinical trials and all of the protocol deviations  that are accounted or not accounted for. But having said that, I think we really should cool. But going back to this whole issue of the population,  we need to make sure, and I said this earlier, that what is the patient population that you have? Because we actually wrote an editorial on this that for a sweeping statement  that everything should be just fever control is probably not fair to the people who are severely injured, right? I mean, you're not going to give erythromycin  and ceftriaxone to somebody with sepsis and shock, right? They may still be pneumonia, but you have to stratify your treatment based on the severity. And that's our problem,  because we don't have a real-time indicator for how bad the brain injury is. All we see is coma. Now, so should we cool? Absolutely, and we should cool early?  The proof of evidence is we should cool early. We should cool to 33. And the reason why ice cap is ice cap, because it's there, it's really 33 is the predominant temperature  that is right now, and that's why we adapted it. But I think in the end, let me just make one more thing, that TTM2, half of their patients actually were connected to a machine,  that when they spike a fever, the temperature machine kicked in. So for us to just step aside, oh yeah, it's normal thermia, let's give them Tylenol and walk away,  that's absolutely wrong. Because the aggressiveness of cooling, controlling this protocol was really still evident for the TTM2 study. I'll stop there.  So should we be trying to find biomarkers that might help us in developing more of a precision medicine approach to these patients, where we can stratify them  based on their severity of injury,  decide on what is the quote best temperature for their acute brain injury,  be it's a biomarker, be it's a neurophysiologic test, or even a radiographic test.  We'll get to the ice cap,  precise cap.  But what are your quick thoughts on trying to utilize biomarkers to try to risk stratify these patients? Because that's what we're doing, right? Trying to take the patients  with the most severe brain injury and give them the most appropriate one,  and titrate, in a sense, I think, I'll call it titrate, your drug of effect, your intervention, which is temperature modulation.  Dave, any biomarkers that  have the highest likelihood of benefiting?  Well, there's two questions there. So first of all, is there a biomarker?  And secondly, is the biomarker gonna show up at the time you need it?  So there are a couple of really promising chemical biomarkers. There are a few, actually. So neurofilament light chain has shown tremendous promise.  GFAP is making a comeback as well. Tau, but first of all,  they may not spike until later. A lot of the studies have looked at them in a serial fashion that they change over time. Secondly, the lab has gotta get the information back to you  so you can know, like, is this a group of interest? And that's really, really tough. I mean, even NSE remains a send-out lab for many, many places  and so it would be great to have a biomarker. So those are chemical biomarkers. There's also imaging biomarkers, which I think actually holds a lot more promise, in my opinion.  I'm doing this work with Rachel Beekman down at Yale, who's particularly interested in the initial CT  and that EDCT, which I've always said, well, don't make any prognostication based on that because it's usually normal. Well, what if it's not normal?  I mean, because sometimes it's like, well, holy cow, that doesn't look good. And that probably is telling us something and something that we haven't really looked at.  We typically use that CT to rule out a hemorrhage or something, but sometimes it's showing us pretty florid hypoxic ischemic changes and why some brains get that  with a certain duration of arrest and other brains don't. I think that's a really interesting question that we haven't answered.  So let me chime in. I think there is one predicate field that we need to learn from. It's called stroke.  So we need to learn from stroke because forever, stroke was like, there was a chronologic clock for stroke, right? When they switch to a biologic clock, things change.  It's like the aspect score and they're doing perfusion mismatches. Why can't we do that for cardiac arrest, right? And I think this whole concept of,  yeah, we cannot do it, it's too soon. When TPA first was studied, they said, no, there's no way we could give TPA in 90 minutes. Now we're doing it regularly.  So if the system sets their mind on it and there's evidence and outcomes, then we could change the system. That's number one. Number two, I love Dave, but I sort of agree  and disagree with what he said about biomarkers. The problem with serum biomarkers is that their goal really is to predict poor outcome and really withdraw care.  So we need to change the mindset of people, really, that we need biomarkers that would tell us that these patients have hope. So we need to change that whole mindset  that neurologists forever, our role was just to say, oh, there's no hope, let's withdraw care. No, we need to change that. And then the last part that I would say  is going back to ISCAP again, right? And ISCAP, actually, it will be using EEG and very early MRI, again, going back to what we said.  If we are determined and we could make it happen, but stepping back again and interjecting ISCAP here, the interesting thing with ISCAP that these studies have not done  is the adaptive trial design, where you have multiple doses in contrast to a dichotomous binomial intervention, whether you get it or not, right?  And as Dave was interjecting earlier, it's either those that are really going to wake up or those that will never ever wake up. The problem is the middle part is huge.  So this is actually part of the biggest motivation for ISCAP is how do we hit the middle part by giving them incremental doses of intervention  and then putting above that the precise gap to define them so that in the future, when we do this, we will not be guessing anymore. Because from Pittsburgh,  they were actually able to show with continuous EEG and CT scan published by Jonathan Elmer, five subgroups of patients that could be identified very early on. So I'll stop there.  And George, I don't know if you have other questions. Yeah, and I'm just reviewing some of the questions that are percolating in. So we've got several interesting questions,  some that are quite specific. But I do wanna, before getting to the  attendees' questions, real quickly, Romer, can you talk about ISCAP?  Oh. I'll summarize real quickly. It's a adaptive randomization clinical controlled trial randomizing patients to different temperatures and- Can I do that, George?  Looking for a dose response curve.  So it's that, but essentially what it is is we will start with three times. So 33 degrees was just placed there because it was a common temperature choice, right?  And we know it's neuroprotective. There's multiple studies showing that it's neuroprotective. ISCAP is not about the temperature, it's not the depth of temperature,  it's the duration of temperature. So what we would do is we would start, so actually when you look at a lot of the recommendations, the trial should be Bayesian, right?  So adaptive Bayesian design, that's ISCAP. So we'll start with 12, 24, and 48. And after the first 200 patients, we will see if there's patients  that are benefiting on the longer scale, then we will keep opening arms there that are longer, up to 72 hours. If they're not improving, then we will stop  and then we'll open the shorter arm. Shortest is probably, is six hours. So if we do this, we will get actually a duration response curve, not just the dichotomous plus minus  that we don't know what's happening in the middle. So, and right now, the sad part about this is when we get our notice of award, guess what happened that week too?  The WHO declared COVID-19 a pandemic. So we were stuck right away. So for like six months, we couldn't do anything because all of the ERs were still limited right now.  But I just want to tip my hat and really kudos to the sites out there. We have 61 sites right now. And as of this moment, we have 362 patients to target 1,800 patients.  And the goal of ISCAP is to keep going on the duration until we hit that curve, that it starts to plateau, that it's no longer getting better. Because at that point, we know that  even if we push the duration, people are not going to get better anymore. But the advantage of ISCAP is because we're giving multiple durations. If we're going to do, for example,  in this Karen Hurst, Jonathan Elmer corollary study, NIH funded, we will be able to identify what are the early signatures on EEG, which can be done at the bedside  and on MRI, all sorts of fancy things on MRI. And we're actually, I'm actually a co-investigator in it. We're collaborating with IBM, the cloud and all of these things and AI,  all of the high tech stuff is poured into that together with the adaptive trial design. So we're really trying to get clinical trials in the 21st century with these protocols.  So, and then the last plug here and then I'll stop. We're now 61 and we're still open. We're still open to sites. If you are interested in either ISCAP or PRECISE-CAP,  email me, my email is ubiquitous. You could find it almost anywhere in the web and we will talk. Thank you. Thanks Romer. And just to emphasize this is an NIH funded.  So it's your and my tax dollars hard at work. So please spend wisely. And I do congratulate you for that monumental lift.  Dave, can you tell us real quickly and then recently received permission to do so, TTM3.  Yeah, it's very exciting. They have already planned and gotten funding just a couple of weeks ago for TTM3. And if you thought normothermia wasn't sexy,  you're not gonna like this at all. So this is answering that question though. Does any fever prevention or control matter? So it's a two by two factorial design  and they're really studying two things. One is avoiding fever with a temperature device for 72 hours and mandatory sedation versus no control of fever until they get to 40 degrees,  believe it or not. Then they can do something with mandatory sedation. And then the other part of the two by two design is with and without sedation.  So temperature control or no, sedation or no? Because I think the sedation issue actually gets at this question of, is it impacting the prognosis of the patients?  Not just our prognostication, but actually are they so influenced? Is the sedation affecting their cerebral recovery? And is it preventing us from seeing  delayed awakening in these patients? So again, hats off to them. They're gonna try to get 3,100 patients in that study. So according to the pace of the prior study,  that'll take about four weeks for them. They're really fast. Three weeks and a half, Dave, with a pandemic.  Yeah, that would be interesting. It's an interesting point about the sedation because there is some consideration that propofol, for example, may be acting as a neurotoxic sedative  and probably is not seen in using volatile anesthetics,  but a whole other topic that's very interesting.  So let's, why don't we take some questions? We are quickly running out of time. And again, I wanted this to be a really interactive discussion. And I think the panelists did that  with bringing their years of clinical experience and research experience. So several questions here. I'm just trying to read through them. We're not gonna get to all of them.  One real quick one. This is a challenge one.  How can we translate this data to the pediatric population?  So whoever wants to connect that one.  So I have a quick answer to that. So there is actually a grant right now that's under revision coming also from SIREN, the same network that supports ISCAP. It's called PD-ISCAP.  So it's the same SAPCA investigators that are doing an adaptive trial design similar to ISCAP but on pediatrics. The leader is Frank Moeller, Will Moyer,  and Alexis Topjen from Penn. So that's coming, that's in the works. They already had the first review and it was favorable. I hope that they get funded.  Another question. Thanks for that.  For Dr. Gio Caden, how do you define the severity of injury other than being comatose or poor GCS? If you think we need to be more aggressive with severe injuries,  is there an extended timeframe we should be looking for?  Extended timeframe for what?  Of course, we'll be dealing with other complications, sepsis, pneumonia.  I guess trying to define severity of injury other than being comatose. So let me answer that this way.  We know that unresponsiveness or comatose state in a neuro patient is brain failure. It's total brain failure. It's the equivalent to heart failure in the heart  or equivalent to the worst ARDS that you could ever have for the lung. Nothing, right? Patient is comatose. When you are at that point, what do you want?  Do you want to hold your punches or do you want to treat them with triple antibiotics and pressers with the equivalent, let's say, of sepsis?  So my take on this is if I was the one having cardiac arrest  and I would rather have the full strength of the hypothermia together with the support, because the key thing that we need to remember  is that TTM-2 or TTM-1 or neither of the study have actually really scientifically shown that 33 is harmful, zilch. There's no data to that.  They indicated that there's some arrhythmia, but the outcomes were still the same, right? And any reputable intensivist will be able to deal with that kind of arrhythmia.  But at the end of the day, you only have one swing at protecting the brain in these patients. If you hold your punches, maybe you don't need it if you're in Lund, Sweden,  or your patient population is not as injured. But if you're in Baltimore, I want to be cooled.  So I want the full court press also, but I don't want to go to 33 degrees. And I will take a little bit of a shot at Romer with the fact that hypothermic myocardium  doesn't respond to antiarrhythmic drugs very well. So if it's at 33, a lot of the things that you use, you might be the best intensivist in the world,  a great cardiologist, but your drugs may not work very well. So you may be in a pickle. I don't think we can say that it doesn't come with some increased risk from that standpoint.  But the study showed that there was no outcomes or functional impact, right? And there were at least six trials that came out, right? So data is data, that's all I'm going to say.  Read the papers and believe me. I'm pretty good at reading papers at this point. But I would say maybe the fact that they were equivalent, there may have been a benefit  that was outweighed by that additional statistically significant difference in the hemodynamically significant arrhythmias. So if they hadn't occurred,  maybe it would have been a positive trial for superiority for 33, you don't know.  Maybe. Two quick questions that are popping up.  Inpatient cardiac arrest, we touched on that. You touched on it a little bit, a slightly different animal.  Can you speak to either including those patients  in upcoming studies and should they be treated just like the patients in TTM-1 and TTM-2 is one question.  Then in terms of the cardiac dysrhythmias,  most of these etiologies are cardiac, although not all. They're going to have cardiac dysrhythmias. And can someone comment on why there was an increased  incidence of complications in TTM-2  in the colder 33 group than in the 37 group?  So I don't know where to start, George. That's like at least four questions. Yeah.  Why don't you tackle inpatient. In hospital. In hospital and I'll let Dave attack the complications higher in the 33 group. We could tackle both, but let me just say quickly  about in-hospital cardiac arrest. That's a different animal, but not really because at the end of the day, the brain doesn't care what your rhythm is, right?  But what the body cares is what are the comorbidities associated. And that's the reason why in-hospital cardiac arrest is treated like a different animal.  Your brain may be okay, but your body will give up. And the very good study with this came out of Pittsburgh with Cliff Calloway's group and Nishikimi in Japan,  that they actually showed a differential response to 33 versus 36 in those patients that were stratified depending on the severity of their systemic injury where 33 was effective.  Now, the key point really here, and this is the Hyperion study, right? This is the Jean-Baptiste Lascareau study at all where they actually showed that these people  are really, really sick. They're the sickest of the sick ever, right? But for those people that will not die, there's about a double chance from 5% over.  So it's like five versus 10% for good outcome for those that survive. And that's what we strive for, right? Let's give them every chance. And at the end of the day,  and this is the other thing that I would like to highlight if there's any take-home message here other than cool is also that this is not a homogeneous patient population.  We have to start looking at the different subsets of patient and in-hospital cardiac arrest in this distinct population that neither TTM1, TTM2, HACA, or Bernard is applicable.  The only thing that applies there is the Hyperion of Jean-Baptiste Lascareau. So we very stick with the results there. And I'll stop there now, George.  Romer, I'm gonna leave you with the last answer and last question. What has Hopkins changed in terms of their temperature for post-cardiac arrest?  Or is that dependent on who is in charge for the patient?  Yeah, so yeah, true to that last statement, we have protocols for 33 and we have protocols for 36. And because there's equipoise with that, we leave it to the clinicians to decide.  Good expression, very good. Well, we- And that's why we're doing ISCAP, right? Because there's that equipoise. Yeah, absolutely. So we're gonna wrap this up.  Thanks to all the attendees. Thank you very much. We had close to 500 registrations.  And again, this is recorded. So in case you had to step away, et cetera, please share with your colleagues. I really wanna thank, a big thanks and kudos to Dave Greer.  Unfortunately, we did not get to talk about Intrepid.  And Romer for your tremendous work with ISCAP and PreciseCAP and centers, it looks like. So keep that in mind.  I really, really appreciate your time and effort in this and to be determined, I think. And we will keep going with trying to figure out what is the best temperature.  So thanks to all the attendees and thanks to the two of you and hats off and happy holidays, everyone.

Video Summary

In this webinar, titled "Targeted Temperature Management," Dr. George Lopez, a neurologist, and his panelists, Dr. Romer Geocaden and Dr. David Greer, discuss the recent study, "Targeted Temperature Management 2." The webinar is sponsored by the neuroscience section of the Society for Critical Care Medicine. The panelists discuss the strengths and limitations of the study, the differences in patient populations between Europe and the United States, and the role of biomarkers in determining the severity of injury and the best temperature for treatment. They also consider the use of sedation and withdrawal of life support in the context of temperature management. The panelists emphasize the need for more research and highlight ongoing studies, such as ISCAP and TTM3, which aim to further explore temperature management in patients with acute brain injury and cardiac arrest. In conclusion, they suggest that temperature control remains important, but caution against making sweeping conclusions from the study, as more research is needed to determine the best approach for individual patients.

Asset Subtitle

Cardiovascular, 2021

Asset Caption

"Should you consider updating your clinical practice related to targeted temperature management (TTM) after cardiac arrest?

The TTM1 Trial results (Nielsen N, et al. N Engl J Med. 2013;369:2197-2206) were published in 2013. At the time, this was the largest randomized clinical trial evaluating the use of TTM in survivors of cardiac arrest. Recently, results from the TTM2 trial (Dankiewicz et al. N Engl J Med. 2021;384:2283-2294) were published in the article Hypothermia Versus Normothermia After Out-of-Hospital Cardiac Arrest, which supersedes the TTM1 Trial results with new and potentially practice-changing data. Current clinical practice that follows the results of the TTM1 trial should now be reviewed in light of new information from the TTM2 trial.

After attending this webcast attendees will be able to:

Compare the results of the TTM1 trial with results of the TTM2 trial
Assess whether these data inform changing current clinical practice for cardiac arrest patients
Create a framework for applying these results to clinical critical care practice "

Meta Tag

Content Type Webcast

Knowledge Area Cardiovascular

Knowledge Level Intermediate

Knowledge Level Advanced

Membership Level Select

Membership Level Professional

Membership Level Associate

Tag Targeted Temperature Management

Year 2021

Keywords

Targeted Temperature Management

webinar

neurologist

study

patient populations

biomarkers

temperature for treatment

sedation

research

temperature control

	Society of Critical Care Medicine 500 Midway Drive Mount Prospect, IL 60056 USA Phone: +1 847 827-6888 Fax: +1 847 439-7226 Email: support@sccm.org	Contact Us About SCCM Newsroom Advertising & Sponsorship DONATE	MySCCM LearnICU Patients & Families Surviving Sepsis Campaign Critical Care Societies Collaborative	GET OUR NEWSLETTER
© Society of Critical Care Medicine. All rights reserved. \| Privacy Statement \| Terms & Conditions The Society of Critical Care Medicine, SCCM, and Critical Care Congress are registered trademarks of the Society of Critical Care Medicine.