Great, well thanks. It's great to be here for Ice Ice Maybe. I promise I won't sing. The goal I think today that Mary Kay and I are going to try to achieve is share some thoughts on where things stand for TTM, Targeted Temperature Management. As all of you may know, probably most of you do know, there's been a lot of controversy around the topic of how to dose and how to think about TTM, especially after cardiac arrest. And so we're going to go through some of that and some of the current research and our perspectives on the problem. A little bit about myself so you know who you're hearing from. I'm an emergency physician at the University of Pennsylvania and I'm vice chair for research in our department. I've been there since 2006 and the totality of my career is focused on cardiac arrest and post-arrest care research. So I've lived and breathed this stuff and hopefully we'll be able to convey some of it to you. Full disclosures, I have received consulting from BD but I have no stock or ownership in anything related to Arctic Sun, but they've just paid me for my appearance today. I think we'll start and by the way some of my slides may look a little funny. We had a little formatting issue so hopefully they'll come through okay. We'll walk through a typical case quickly, although all of you as critical care providers that we almost don't need to do this, but just to highlight what we're talking about when we talk about post-arrest care and the kinds of patients we're thinking about. So in this case we have a 57 year old male collapsed at home. Bystander CPR was provided and they were brought to the ED after unsuccessful defibrillation. So that is not an atypical case and of course as many of you know a witness shockable arrest is really sort of a the most viable or potentially viable of arrests. So I like to say it is we you know no one should die of witness v-fib arrest. That's an aspirational goal not a realistic one but but really witness VF is something we should work hard and they do so in this case and eventually the patient is resuscitated, has a negative head CT and an ECG that does not suggest STEMI and the patient is dispositioned to the MICU. So this is a fairly typical story that you've all had and it highlights the fact that many of our patients at least in the United States have prolonged resuscitations. So they tried to resuscitate in the field, they failed, they brought them to the ED. So this was maybe a 20 or 30 minute downtime which is not atypical in the U.S. and this now really begins the next phase of care which is a brain disease. We call it cardiac arrest but at this point we have now shifted to how do we restore health to the brain so that this patient could be discharged. And for a large number of years we've had this prevailing notion that one of the most protective things for the brain is targeted temperature management. The old term of course was therapeutic hypothermia. That term has changed and if if you're not sure why we will certainly explain that shortly but from a number of decades of laboratory research the idea was if you lowered the temperature to 33 and I the animations are all messed up by the format change that that was supposed to follow along nicely but there you go. But the notion is if you lower core body temperature to 33 Celsius, that was the target temperature, and then rewarm after a period of time this put the brain in a better state of health. And and I don't have time to go through all the pathophysiology but suffice it to say it's been very very well mapped out in many laboratory experiments, reduced brain edema, less glutamate toxicity, better mitochondrial function, etc etc. So cooling is really good for animals after cardiac arrest. Well this needed to be studied of course in humans and there were a number of landmark studies in 2001 and 2 that suggested that hypothermia or cooling to 33 Celsius improved neurologic recovery after cardiac arrest. I show you three the three main studies here and and the red percentages are really where to look. This is the number of people who survived with CPC cerebral performance category one or two. That is to say they were walking and talking. Survival of course is not a good enough metric for any of us. We don't feel good about ourselves sending people to an LTAC tracked and pegged. So they only scored it a success with neurologic recovery. And in all three of these studies there was a large improvement in survival. In the HACA study they looked six months later and found this was durable. So it wasn't a transient phenomena but at six months all but one patient were alive with functioning brain. So that's all very nice and tidy. But those studies all looked at V fibrous and one question that was a controversy at the time years ago was whether or not this therapy worked for patients with PEA or asystolic arrest. As you know these days the majority of patients are actually non shockable rhythms and and we just didn't know for sure whether there would be a benefit there. And until this study came out a large French study known as the Hyperion trial. And in the Hyperion trial they looked at patients with asystolic or PEA arrest initially. So these patients were much sicker and and as we all know they have a much lower survival rate. But the reasoning went lower survival rate potentially more benefit from cooling because these are brains that are more injured. And indeed what they found was better neurologic survival statistically significant better survival with cooling. Now it wasn't overall survival. Overall like do you make it out of the hospital alive was the same. But if you survived you had better brain function. So in a way that's sort of exactly what we would have expected that cooling mitigated brain injury. But if you were more abound after cardiac arrest it would not bail you out of in-hospital death. So at this point it made for a very clean story that regardless of initial rhythm you should receive TTM. And this indeed is what the guidelines stated in 2015 and again reiterated in 2020 that all post arrest patients need to be considered for targeted temperature management. That didn't mean they all needed to receive it but they all should be considered especially those patients who are not waking up after cardiac arrest. That is to say if operationally defined as a Glasgow motor score of not being six. That is if someone could give you a thumbs up or open their eyes to command in general we believe those patients do well. But if they do not follow commands they need TTM. Now this was all a very nice clean approach that prevailed for a large period of time until a pair of studies came out TTM-1 and TTM-2. And I'm going to go into this in a little bit of detail. This is the TTM-1 trial. At the time it was just called the TTM trial but now we know it as TTM-1. And this was a published out of Scandinavia, Nicholas Nielsen and colleagues. And they asked a very simple question which was do we really need to cool to 33 or is aggressive fever avoidance enough? Now a little bit of context. We know that after cardiac arrest the brainstem is dysfunctional and many people get neurogenic fevers. So by managing patients aggressively with cooling devices with technology to keep them at 36 we might get the best bang for the buck and that we avoid these neurogenic fevers but we don't go through all the trouble of cooling to 33. That was the notion. And what they found, well I'm going to skip this slide and get back to it later, what they found was survival was the same at 33 or 36. Now this was the start of our controversial modern era of knowing what is the correct dosing for TTM. Now it's important to note that in their trial, and these are the two groups, they had a very very high rate of bison or CPR, 73%. They had a very low rate of circulatory shock post-arrest, 15% or less, and a very very high STEMI rate. Most of these people were STEMIs, well not most, but a very large number about 40%. So I put that out there to say that this population looks very different than what I see at Penn and I think what many of us see at our US hospitals. There are many reasons why this may or may not be the case, we don't have time to get into it, but one of the most important questions in any RCT is is it generalizable to the patients we see at our hospital? And we'll get back to that in a little bit more detail. Now they followed up with a second study known as the TTM2 trial, came out fairly recently, where they said okay if 33 and 36 give the same results, maybe we don't even need 36, maybe we can compare 33 to normothermia, which they defined as anything under 37.8. Now it gets a little confusing, they defined operationally this as if you were under 37.8 you could do nothing, if you climbed above 37.8 you could apply a temperature cooling device at that point to stay under 37.8. So it's a bit of a hybrid approach and one thing that gets buried a little bit on this study is almost half of the patients in the control group ended up with temperature cooling devices. So it's important to remember this wasn't truly you know 33 versus nothing, it was 33 versus a hybrid where half the patients got a temperature control device and half did not. What they found was again that the survival was the same at six months and neurologic survival as well. So this amplified the controversy because now the question is being asked all over the world, do we have to cool to 33, do we do TTM at 36, do we do TTM at normothermia, we don't know. Which by the way is why the broader term TTM is more applicable than hypothermia. I think everybody agrees that therapeutic management of temperature after cardiac arrest is important. TTM investigators, everyone. The question is not whether we do TTM, the question is what temperature and do we need to use a device or not. And in the next set of slides I'm going to hopefully explain to you why it is my belief and of many folks in the field that we have to be very careful to throw out 33 as a therapeutic option and very careful before we throw out targeted temperature using a device. And I'm going to walk through some of the logic of why I believe this to be true. First there is several decades of animal literature focusing on post-arrest TTM showing a benefit. And so this literature is actually very consistent and supports the notion that not only is TTM useful but there's a dose-effect relationship. That is the deeper you cool the better. The literature is very consistent. So if you're a dog, a pig, a mouse, a rat, TTM there's good mechanistic biology showing why it might work. But as we know literature in the animal world doesn't always translate over. So then we have to ask ourselves well what is the overall picture of the RCTs? And we have three RCTs showing a benefit of 33, two RCTs, TTM 1 and 2, showing neutrality that they're equivalent and no RCTs showing substantial harm. By substantial harm I mean worse clinical outcomes. And so if you're faced with a patient before you in the ER or ICU who is in extremis, very sick, risking long-term durable brain injury and you say to yourself well some evidence supports it, no evidence suggests harm, two trials are neutral, I would say that a very simple sort of simplistic level I would want if that family is saying I want everything done for my loved one and there's some evidence of benefit, to me it feels problematic to say well because there's two neutral studies I won't do anything for that patient. And so this is sort of a summary of all of these studies lined up. But I think that the other important thing to keep in mind is real-world experience. So there have been a number of studies published now that have looked at hospital experiences when they switched away from 36. This is one from Melbourne, Australia. They switched to from 33 to 36 after TTM 1 and their outcomes worsened. They had worse survival after that switch. This study from Nick Johnson and colleagues in Seattle, exact same thing. Their single hospital experience, they switched from 33 to 36, their survival worsened, they switched back to 33. Now observational studies, not RCTs, many things could be at play but there are now four such studies published showing that switching to 36 worsened outcomes. We don't know the mechanisms but I think there's a cautionary tale that we shouldn't be too hasty and I'm gonna try to give a metaphysical sort of view of this. This happens in critical care all the time. Witness for example the vitamin C and sepsis story. You know a trial will come out showing this is the best thing ever, we should all switch to it and then you sort of go through this cycle where other studies show well it doesn't work and how could we be so foolish and then eventually, and this is through all fields of medicine, eventually reach an equilibrium shown here on this curve at the end where you say well medicine is difficult, patient care is difficult, in reality this therapy works for some patients, maybe less well for others. Of course that's a messy storyline that people don't like but that's often the reality of these therapies and so the path less traveled is often the correct path and if you want an example of why I believe this to be true, I have a few examples. This is from Cliff Calloway and colleagues at UPMC. They have a, UPMC is a very large hospital system. Their physicians formed a very nice natural experiment. Some believed quote-unquote in 33, some believed in 36 and they did very careful statistical propensity matching of the patients at their hospital systems who got 33 and 36 and they looked at injury severity, how sick were these people and without going through the details of this difficult to read slide, I'll just tell you the bottom line. They found that the patients who showed more evidence of neurologic injury and instability did better at 33 statistically. The people who are much less sick did better at 36. So this suggests what we know to be true in critical care. Patient care needs to be tailored. Imagine if I asked you as critical care providers, should I use pressers and sepsis yes or no? You would say well that's not the right question. The question is for whom should I use pressers? And I think the same logic applies in TTM. Another example of this, this is out of Japan, same sort of findings. They used a different injury severity scale known as RCAST. Details not important, involves lactate and bystander CPR. It's sort of a made-up, the experimental metric of injury severity but they found that there was a sweet spot. Patients of moderate injury did better at 33. Patients who are too sick it didn't matter. Patients who weren't so sick it didn't matter. Again, no population in their study did better at 36 but so there's no evidence of harm from 33 but in one sub-population they definitely did better at 33 versus 36. If you need a third example, this is one out of the Netherlands where they looked at EEG and they found that patients with moderate encephalopathy on EEG did better at 33 than 36. So three and there's a fourth study that's also shown this now that's come out but at least these three studies in the slide deck have shown that when you look a little bit more specifically at the more injured patients they did better at 33. Now we have to look back at TTM 1 and 2 and remind you that they have a very high rate of bystander CPR, a very low rate of shock. I'm not in Scandinavia or Europe where most of these patients were enrolled. I don't know a lot of the specifics but I can tell you that things were different in TTM 1 and 2. They really, they're internally consistent. They both had a very high rate of bystander CPR, high rate of witness arrest, low shock rate. So one might say well all of these data fit together very nicely. The way to explain these trials and these observational studies are some people benefit from 33, the sicker ones. Some people may not matter and that sort of is a grand unifying way where all of the data sort of makes sense in totality. I'm going to skip this because I've sort of explained it and actually I'm going to skip this because I want to make sure we leave time for questions. One question that comes about is the duration of TTM. There's another controversy. There's some evidence suggesting in the animal lab longer TTM is a benefit. This is the one RCT on this topic that showed a trend towards better survival with 48 hours of cooling versus 24 but it was not significant. So a big question that remains in the field is how long to use TTM for and there's a major trial in the U.S. right now called IceCap underway. We're an IceCap site looking at duration of TTM therapy so stay tuned we may know more soon. An important thing for many of you folks to realize is that this is now something that the Joint Commission is going to be looking at. The Joint Commission which as you know accredits U.S. hospitals has now incorporated in this what they call their R3 report which is just sort of one of their updates to their accreditation that they're now going to be looking at their accreditation visits and whether hospitals have a post arrest care protocol and are using TTM. Now they haven't specified temperature which I think is appropriate because this is still a controversial area but they want to make sure that at least the guidelines are being followed and hospitals have TTM protocols to at the very least avoid fever. A little bit of a shameless plug if you want to learn more because it's obviously a very brief lecture we've started a educational program at Penn called the TTM Academy because we've recognized there's a big implementation gap at many hospitals on the science and implementation of TTM and we're actually oh this slide is not updated my bad May 21st. May 21st is our next course. It's a one-day workshop CME CE workshop on post arrest care held live at Penn. If you want to find out more feel free to check out this website PennTTM.com or visit us. Full disclosure I make no money from this. It's not a business even though it's got a dot-com address just a CME program through Penn but we have a much more case-based learning and in-depth educational experience around this. So in summary from my talk certainly we all I think believe cardiac arrest is not hopeless. When is Damar Hamlin's remarkable recovery in Cincinnati very recently? At the very least fever avoidance is crucial and experience has shown that fever avoidance is very difficult out of device. To wit in the TTM 2 trial half the patients ended up with a cooling device to manage their temperature. I think that TTM at 33 is still relevant for a number of patients after cardiac arrest. I can't tell you exactly who but we know that more injured patients may require TTM at 33 if you believe the studies. It's important started early and it's important to know that Joint Commission is going to be looking at this therapy at your hospitals. And with that I will stop and maybe we'll turn to Mary Kay and then do all the questions at the end. Does that sound good to you? Yeah okay great. So Mary Kay this. Thank you. Can you hear me okay with this mic I have on? Yep good. All right well it's a pleasure to be here with you and I'm going to look at the care of post cardiac arrest in terms of bundles of care and how we came upon creating the bundles of care. My disclosures. So I am getting honorarium for speaking from BD NeuroOptics and Cerebel. So post cardiac arrest infusions or post cardiac arrest syndrome was a definition first proposed by Nolan in 2008 defined as a unique and complex combination of pathophysiological process including four key elements. So these key elements lead to pathologic processes that go on not just during the arrest but for the minutes to days after the arrest. And so how we respond to that is very important. As Ben just talked about the Joint Commission and the AHA ECC had had a series of meetings where they were trying to improve the care nationally of post cardiac arrest patients. And so they did release these new performance standards. There are two standards specifically related to does your hospital have a protocol that defines not just TTM, does it define the neurologic care, does it define the cardiovascular care, the pulmonary care, so all the systems. Do you have a written protocol that's been developed by your multidisciplinary team? And secondly do you have a protocol that addresses neuro prognostication? And so they're not looking for one way to neuro prognosticate, they're looking for a multi-modal approach. And have you defined that in a document in your institution? Now at Mission Hospital, I'm from Southern California, I work at Mission Hospital which is a American College of Surgeons trauma center or a comprehensive stroke center, a very advanced cardiac care. We had had a TTM protocol for years, since 2006 I wrote the original one. But did we have, we didn't have a protocol that was all-encompassing of all of the most current literature and systems. So what we did is we we brought together physicians from all the different specialties, nurses, and given those standards and these performance monitoring standards which are very specific. When the Joint Commission comes they want to know are you keeping track of your data? And I guess that's the one challenge I would say to anybody who takes care of cardiac arrest patients. If you are switching from 33 to normal thermia, whatever you decide to do, you need to keep track of your data and the outcomes of those patients. Because you may not realize the change if you change your practice or go back. You need to follow those patients and see what your outcomes are. And so part of this is related to the cardiac arrest itself but also in post-resuscitation care. So we developed 23 PICO questions. We had reviewed a hundred and seventy articles from the literature at most current as this happened in January, February, March of 2022. And so the nurses, there were 29 nurses, there were 12 physicians that were part of this as well as pharmacists. And we came together and debated and agreed on how we were going to manage every system of care in that post-arrest patient. So we understand that that immediate post-recession care following a turn of spontaneous circulation is focusing on mitigating the injury, not just what's gone on with the heart, if the heart was the primary event, but what are you doing for the brain, for the lungs, etc. We understand this is not about the heart, that it is very much important to the brain. I'm a neurocritical care clinical nurse specialist, so I am all about the brain. Yes, the heart's important, but for me it's a pump, pumps the blood to the brain. So we needed to get the multidisciplinary input and then structured our protocol into the immediate stabilization period, so the first 120 minutes after return of spontaneous circulation. We set time goals as well as interventions that need to be done. So oxygenation and ventilation, we set target goals with SpO2, PaCO2, and PaO2. We established target goals for blood pressure, so starting with a systolic BP greater than 100, but really looking for a map. Now the map you see on here, you're going to go, whoa, a map of 80, that's higher than the American Heart Association 65. We reviewed a number of articles that looked specifically at neurological outcome with blood pressure, and those articles pointed to a higher map, so the more severe the neurologic insult, those patients with higher maps did better. I understand there are studies like the box trial that came out this summer that said, oh, 65 is fine, but they didn't really target that at the sickest, the most neurologic sick patients. We talked about a target goal that 12 EDKG within 10 minutes, TTM candidates, if they are comatose, needed to have TTM initiated within 60 minutes, and if they are a PCI candidate, having that cardiology team on board. So after a quick airway breathing circulation reassessment and securement, after that, what is the Glasgow Coma score? If they're awake and following commands, you're going down one path. If their Glasgow Coma score is 3 to 8, they're patients not following commands, we knew that we had specific time goals and targets that we had to hit. So our consultants from all the different disciplines would be consulted by the emergency department team. Airway breathing circulation, so intubating the patient who's comatose if they're not intubated during the arrest, getting blood gas, making sure that we titrate down the FiO2 as soon as possible, and then targeting PaCO2 between 35 and 45. Vital signs and ECG rhythm, getting your cardiovascular support in, your 12 lead done, peripheral IV access, getting your labs. Targeted temperature management, we looked at the literature, we looked at all the studies that Dr. Abella just presented, and the studies that pointed to, you know, changing from 33 to 36. We had always historically been a 33, but 36 was chosen if we had a trauma patient, bleeding patient, we would go with 36. We've been following our outcomes in TTM since 2007, so I can tell you year by year, by rhythm, what percent had a CPC 1 to 2. So we knew what our data was. So after looking at the literature, our physician team and the nurses that were part of the lit review, we decided that a TTM of 33 was our go-to, mainly based on, yes, the more severe the neurologic insult. If they were hemodynamically unstable, if they had issues with bleeding, then 36 would be the target. So following that, with targeted temperature management, we came out with those recommendations, and that was put into, you know, using a risk stratification to select optimal TTM strategy. The next was also looking at the neurologic priorities in the first 120 minutes, so having that neurologist be involved very early in the post-arrest care. After consideration of TTM and getting the TTM started, we then started to look at, well, what about EEG monitoring? So for many of you may think, well, EEG monitoring shouldn't be a priority, but our neurologists, our critical care neurointensivists, and our epileptologists said, yes, it is, and seizure monitoring should be initiated as soon as possible. So we have a goal within 30 minutes of return to spontaneous circulation in comatose patients, we put a headband EEG on until we can get the full montage EEG started in the critical care unit. So they get started in the emergency department, make sure that we have a non-contrast CT, and if there's any traumatic mechanism involved, we'll get a c-spine. Cardiac evaluation in the ED starts with the, after the rhythms, getting a start echo, and having cardiology determined, and this, again, was a point where cardiology had to come together. There's a lot of discussion about immediate going to the cath lab versus waiting and risk factors, so we let the cardiologists sort of slug it out and bring to us what were their recommendations, and then transfer to the ICU. We also had interventions for the Glasgow Coma Score 9 to 15 patients. So we ended up with, this is our 120 minute bundle, and this bundle defines the different priorities in that post-arrest patient. So we're not just looking at TTM, we're looking at oxygenation, ventilation, circulation, we're looking at metabolic derangements. TTM is a component, just like early cardiac intervention. Neurologic care has to be addressed at the beginning, and also family and caregiver support. Then we turned the protocol into the definitive critical care management time period, so we had established our pulmonary and ventilation outcome parameters or target goals, choosing a low-volume ventilation strategies. We looked at the papers that were published on optimal sedation agents, and elected to go with propofol and fentanyl, and an intermittent neuromuscular blocker. And if you're interested in these slides, I'm happy to send them to you. All the articles that we used are cited on the bottom. It's very small because there are a lot of articles. My email is badernk, it's on the last slide, at aol.com, and I'm happy to send it to you. The mean arterial pressure discussion, where we decided on the map of 80, came from a lot of these articles that were published in the last five years, looking specifically at patients with that more of a neurological hit, where's the optimal mean arterial pressure. So we decided on 80, except there's a caveat. It says if they wouldn't tolerate, if there would be more harm, then a map of 65 is appropriate. So if the cardiac or the cardiologists are going to contribute their thoughts into the discussion of where the optimal map should be. We also reviewed articles related to serial echocardiograms, invasive catheters like Impella and balloon pumps, nutrition requirements, optimizing hemoglobin, DVT, prophylaxis, and steroids. Our protocol also addressed neural assessment and monitoring and management of cerebral edema, because how important it is to define, especially if these patients are cared for in the cardiac ICU, what are those neural monitoring priorities. So making sure that we had defined the neural assessment, that we use pupillometry from the emergency department throughout the care, as well as other forms of monitoring like EEG. So the neural assessment monitoring, we have non-invasive monitoring with pupillometry, near-infrared spectroscopy, EEG, and TCDs, and interventions, which is just the interventions to reduce intracranial pressure, the effects of cerebral edema. The seizure component is quite significant, and so understanding that there's, that is a big risk in post-cardiac arrest patients, and so getting EEG monitoring started as soon as possible, so that 30-minute EEG, and then continuing that on for several days to make sure that we are addressing the electrical activity of the brain. The last major component was neuroprognostication, and so neuroprognostication means that we need to look at every patient. First off, never happens before 72 hours after return to spontaneous circulation, all the meds are off, and then how are we going to approach it? Clinical exam, SSEPs, EEG, biomarkers, so we draw serial neuron-specific analase levels, imaging, both CT and MRI, and then it is a group discussion with the neurologists, neurointensivists, epileptologists, and pulmonary critical care, as they then approach the family and caregivers. So this pretty much defines for you the, how we enact that neuroprognostication. Lastly, we developed a bundle again, these are the bundle elements related to the care after two hours, while they're in the ICU. We use the same major markers of oxygenation, ventilation, cardiac, neuro, TTM, seizure surveillance. We have the interventions and the highlights of what we want the team to do, and then we have the parameters that are monitored for those patients. Lastly, there are performance metrics. The Joint Commission wants to see these performance measures. They have specifically directed that you should have data. I've been the chair of our resuscitation committee since 2000, so for 23 years. I have a report, we follow Utstein's criteria for in-hospital management. We don't participate in a registry, per se, but I have every single, we review a hundred percent of our in-hospital cardiac arrests. So every one of those patients are going to be reviewed by a multidisciplinary team, to see where were their opportunities to improve. With that, my email is here. If you are interested, I'm happy to send you the bundles that we have. We have them on separate documents. Anything I can do to answer your questions, I'd be more than happy. I think we're going to turn things over for some questions and discussion.

targeted temperature management

TTM

cardiac arrest

optimal temperature

individualized care

brain injury

post-arrest care