Dr. David Beiser discussed targeted temperature management following cardiac arrest.
DR DAVID BEISER: I'm Dave Beiser and as Ira said, I am the self described doctor cool. My pager is two six six five, so just two c-o-o-l, it took me about five years of stalking that number before I was able to get it. But now that I've got it you can't get it away from me. So OK all right so today what I'm going to talk you guys about is what we used to refer to as therapeutic hypothermia, how many people out there have cooling programs at their hospitals? Of those folks how many people have cooled an arrest in the last let's say two weeks? Good that's better than expected. The national statistics would suggest that our cooling rates are still really, really low. OK so a lot of programs now have a cooling protocols but the truth is very few patients are still getting cooled. I know that it's taken Herculean efforts at University of Chicago to cool patients. I've been doing this for about maybe 10 years at this point. I started cooling patients in 2004 and to keep the momentum and get and make sure that we cool every eligible patient I'm essentially on call every night so I've taken 10 years of continuous call, that's awesome. But that's kind of what it takes. You need somebody to kind of take this over as a champion. So just before getting too into the details I don't really have any relevant disclosures. I've got a couple grants they aren't related to cooling I haven't taken any honoraria. I was part of a cooling trial, this is a device that was cooling myocardial infarctions, but that is over with it at this point. OK. So what I'm going to talk to you today about I'm going to give you kind of just a general overview of kind of the problem, cardiac arrest you probably already know most of that stuff. I'm going to you a little bit about the therapeutic hypothermia trials, the relevant ones, that you should pay attention to. There's a lot of information out there you don't really need to pay a lot of attention to. We'll look at a very recent trial they may have heard of from last December, the Targeted Temperature Management Trial by Nielsen that created a lot of hubub in the popular press and in the blog sphere and in the Twitter sphere about kind of cooling and the word in the popular press was, cooling is dead. OK. We should no longer be cooling, and this trial is kind of a giant reversal of therapeutic hypothermia. And we've seen a lot of reversals in our practice, anybody who's practiced for more than a decade is probably as experienced, there's therapies they were in favor ten years ago that we now we no longer do or we think are harmful. OK. Today we'll try to kind of get at the bottom of this and see if therapeutic hypothermia is one of those therapies. We'll look at the results and then we're going to try to integrate all of this information into kind of a practice recommendation for you and I'll just kind of what we're doing at the University of Chicago. So first of all, this should be familiar curve to anyone who's either working emergency department or in the ICU. This is the survival curve over time for cardiac arrest. And as you can see the 80% problem is just in that first few minutes where, from kind of the arrest to ROSC where you've got about a 10% per minute decrease in survival rate for an untreated cardiac arrest. So we lose most of our patients here. And most of the research over the years as really been focused on these moments right? So the early access to difibrillation, bystander CPR, that kind of stuff has really been the focus, as it should be. There's also this huge opportunity. So that 30% of folks are will achieve ROSC in the best systems so that would be Seattle, Richmond Virginia, Houston places like that, that have really high survival rates for out of hospital cardiac arrest or initial ROSC rates. They would not be unfortunately this point in Chicago, but we're moving in that direction but here's the problem. Of these folks most of them die within the first 24 hours. And then ultimately only 5-8% of folks get discharged from the hospital. And that's not even, these are not neurologically intact survivors necessarily. OK? So these are really dismal numbers. So there's an opportunity there. This is the opportunity that we have with cooling. OK? It's relatively small but it's actually within our control. A lot of this happens and it's outside of our control. It certainly happens outside the hospital, but it also, there's a lot of social barriers that contribute to this that we just can't get through very easily. So we have a lot more control over this environment. So this is the two original RCT's randomized control trials that kind of got us going back into this idea of using hypothermia. Hypothermia has been around for a long time, but it's been in our favor for over 100 years. But what really took off was in 2002 there were two trials that were published as companion pieces in the New England Journal. One was by the therapeutic hypothermia group, the HACA trial and then the other one was by Steven Bernard out of Australia. And what they did was that they took very well selected patients cardiac arrest patients. These are patients that had ventricular fibrillation arrests OK so initial rhythm was either VF or VT who had witnessed arrests out of hospital and achieved ROSC and were comatose upon return of spontaneous circulation. And what they did was they randomized them to two different groups. One group, the normal thermia group, they just let them, let their body temperature just roam free. OK. So they didn't do any control measures at all. They didn't put warming blankets on they didn't put cooling blankets on, they just let the temperature just go as it would normally following an arrest. The other group they cooled. And they used a variety of modalities but primarily used blankets OK or special cooling blankets, ice packs, things like that. And so this group was cooled to a target temperature of 33 degrees. I want you to notice a few things about this curve, I'm sorry, the Bernard trial they did the same thing. They got the intervention group colder a little bit more quickly as you see, that's this red curve and they didn't keep them cold quite as long. And what they found is that their survival rates OK so this is the relative risk of a good survival so it's difficult to think about kind of a good outcome is being a risky outcome. But this is how it's expressed in the literature so the relative risk of a good outcome was 1.5. This is essentially doubling your risk of having a good outcome. The Bernard trial got them colder little bit more quickly and actually had a higher risk of a good outcome. And this is just the survival curve for the HACA trials and as you can see the long term survival here on the y-axis, and this is the number of days as you can see there's a survival benefit the persisted out to 200 days following the arrest. And with this information, we'll go through it with a little bit more detail so you can see that the HACA trial in two different groups and the relative risk here of being alive at hospital discharge was 1.5. Bernard as I said was 1.75. But then six months later the HACA trial still maintained a relative risk of 1.4. The interesting thing about this, you can use these statistics and turn them around and calculate this thing called the number needed to treat. So this is the number of patients that you would need to induce therapeutic hypothermia on, to have a good outcome. It's a really important number when you're thinking about devoting resources to this. So think about some of the things that we do in the emergency department or in the ICU and what is their number needed to treat? So how about aspirin? The number needed to treat for aspirin. It's about 50 so you need to get 50 people an aspirin to actually have an improvement in outcome. OK heart transplant, number needed to treat? One. OK so you have a better outcome with that patient but you balance that with the resources. So the aspirin costs nothing. So we give it to as many people as possible because somebody's going to get a benefit, OK? Not everybody, but somebody's going to get a benefit. Heart transplant, very expensive, right very expensive intervention, number needed to treat? One. Hypothermia, inexpensive very. Is it a risky intervention? It's not a heart transplant right it's just throwing a cooling blanket on somebody. We only need to do it to five to six patients to actually have an impact on somebody's life and I think that's one of the things that I'd like you to take away from this. That's what this data suggests. Now there are some limitations to the HACA trial at least. This was done in Europe so they do things a little bit differently. First of all these were only VF, VT patients, relatively small trial obviously they weren't blinding the intervention. You can't really blind a practitioner to the fact that one patient is getting cooled and the other patients is not getting cooled. It's not like giving a drug therapy for example. There was more diabetes and coronary artery disease in the control arm. So that could have biased things and that's probably one of the more damning parts of this trial and finally 20% of these patients receives thrombolysis. So they received TPA or something similar to TPA, following arrest. That's not something that we commonly do certainly in 2002 we weren't doing this, to our cardiac arrest patients. And we still aren't. In between like then and now there's been a trial where they gave TPA to cardiac arrest patients, and they found out that it made no difference. So that trial was stopped. It was the TROICA trial. So based on the strength of these two RCT's, the American Heart Association came up with a consensus guideline, and this was back in 2010. This is actually the second time that they had looked at this. In 2005 they looked at it and in 2010 they strengthened the recommendations. And they essentially said that comatose patients that are adults that have returned spontaneous circulation or ROSC, I'm just throwing ROSC around without actually defining it, sorry about that, following out of hospital cardiac arrest, a VF arrest should be cooled to 32 to 34 degrees for 12 to 24 hours and they made it a Class I recommendation. Which means in their language that this is a really good thing to do. It's the standard of care. Anything less than this is malpractice. It's a very strong recommendation. And then they said, well therapeutic hypothermia may be considered, may be considered for adults following in hospital cardiac arrest or out of hospital cardiac arrest of any initial rhythm. And they made this a 2 b classification recommendation which essentially the way I translate it is, do you have any better ideas? What's your plan? Right are you putting them on Hospice care? Or are you just going to hook them up to a bunch of machines and start the billing, the billing cycles? Right which is essentially what you're doing, it's high tech hammering and if you're not doing something that has some evidence behind it to improve cardiac arrest survival. Right? So this is back in 2010 and about that time. They also added this extra link to the chain of survival so we know the 911 early access to bystander CPR, early access to difibrillation through AD programs ACLS care via the ambulance and then finally kind of post resuscitation care bundle and they recommended that hospitals have an integrated program of post resuscitation care. And integrated meaning you can't just have the emergency department receiving the patient and then admitting the patient and kind of cleaning their hands and saying it's your patient now. You need to have a full team. And that's what we do at the University of Chicago. We actually have, when a cardiac arrest comes in we have a page that goes out our cardiology team, our cath lab gets, not activated, but they get alerted that there's a cardiac arrest being worked in the emergency department so you better get ready, the chaplain gets alerted, we get a pharmacist that comes up to help out with the code, the tower, the ICU bed manager gets alerted and then I get alerted as Dr Cool so that we all for one brief moment, we focus all the resources of the institution on this one patient. And by doing that we hope to improve overall survival rates. This is a tough slide look at, but you don't really need to read any of this. These are all trials where over the last 10 plus years people have have used therapeutic hypothermia to treat a variety of patients that do not have VT or VF arrests, so these would be PEA arrests. OK other kind of less well selected cardiac arrests. It's all observational data, so they're not really trials, they're studies. OK there's no randomization they're just for the most part before and after studies. We were doing this we created an intervention, we let the intervention go for six months, a year we compared our results to historical results. So classic kind of before and after observational study and what I want you to notice is not kind of all this or any of the text here but just the dots. OK So the dots basically show kind of your mortality risk and if you're to the left here, you have kind of improvement, the right you have a worsening. And as you can see the balance of the dots kind of tends to kind of go to the left of that line. Same with kind of the neurologic outcome poor neurologic outcome risk. So you want to have a decreased, decreased risk of a poor neurologic outcomes sorry for the double negatives in there but that's how it's displayed. So on the balance, the dots tend to be on the left side of that line. This observational studies low quality data, but that's what we got. OK. So we've got this data we've got these two RCT's we're still kind of running ahead. Then this came along, last December. This is a group out of Norway, where they randomized patients to either 33 degrees or 36 degrees and unlike the original hypothermia trials, the control group, if you're paying attention is controlled temperature at 36 degrees. They didn't let the patients roam free OK, they stuck the temperature right the 36. They looked at out of hospital cardiac arrests that had a presumed cardiac etiology. So that's a slightly different selection criteria. They looked at all kind of initial rhythms except asystole. So they didn't select the patients as closely as a HACA trial. They all had ROSC within 20 minutes, that's a little bit different than the HACA trial and then they randomized them for 28 hours of controlled temperature and then they looked at mortality. It was a big trial for cardiac arrest. 939 patients, roughly three times the size of the original HACA study. And it was done really well. I saw this and I thought to myself is this the big reversal is this like my first reversal of my career. Unfortunately maybe the reversal happened in the one area I was most interested in, so that was a little bit of dark times for a week, until I really understood the study. So here's what they did. These were the temperature profiles, this is the control group it kept them at 36 degrees. Now I don't know if you guys remember, but when I showed you the HACA temperature profiles, the control group kind of went like this. Right? And in fact most of those patients, many those patients spiked a fever. We all know this right? If you're an ICU nurse you know this right? Sometime in the first 48 hours many of these patients will spike a fever if they're not being cooled and it's not necessarily sepsis it's more of a sterile sepsis. These patients will have a kind of a large outpouring of inflammatory mediators. OK so it's like sepsis but it's the sterile substance there's no focus of infection. It's just a bunch of cytokines being kind of created by this ischemia reperfusion injury that's happened, the whole body has had ischemia we reperfused it and it started just making these inflammatory markers. So every tissue is just elaborating inflammatory markers that's causing the fever. But when you keep them at 36, you avoid that so this is more fever avoidance, is really what's going on here. And then the control group, which they kept at 33 degrees. So slightly warmer, and this is what their outcomes were. I don't know if you can see it, but it doesn't really matter the outcomes were the same in both groups. OK so there's a green line, which shows which is a control group the blue line is the intervention group. The lines look exactly the same. There's no significant difference. So we're done right? No more therapeutic hypothermia. OK thank you. Well let's look at it a little bit more closely. So what they found was a relative risk of all cause mortality at the end of the trial relative risk, was one. Which means no difference. And the relative risk of a poor neurologic outcome at 180 days was one, doesn't matter. You're wasting your time, don't cool these patients. Well let's look at the survival a little bit more. So here we have the HACA trial, hypothermia trial. A couple things that you'll notice is certainly the initial kind of like ROSC rate right here was a little bit higher in this group. But you can see it it's very striking the differences. The normal thermia group actually did not do quite as well here as the normothermia group in the Nielsen targeted temperature management. So this is about 0.5 here this is under 0.5, so something has happened in their interim. Clearly their survival group here there's a difference between this group and that group. So your two control arms have a difference in survival, suggesting that there's something fundamentally different either about these patients or about the control group care. Now, I think I probably emphasize this enough at this point but the it's really difficult to compare these trials because they really tested two different hypotheses. The first one was hypothermia versus the standard of care. The TTM study they looked at hypothermia versus control temperature at 36. So we shouldn't really be comparing them, head to head with this. And the trial was not a negative trial but what we call a neutral trial, showed no difference. A negative trial would have shown harm. All right. I want to point out a few of the differences between these two studies. So for the HACA trial they had-- OK the number of VF patients approximately 96% to 97% of them were VF patients and the number of patients that received bystander CPR about 49, 43% to 49% In the Nielsen study, 73% of these patients received bystander CPR. Does that sound like Chicago? Does it sound like Indiana? Does it sound like Illinois? No. Right? How many, what percentage of our patients get bystander CPR? It's vanishingly small we can't even measure it. OK so 73% of patients in Norway get bystander CPR, which is just awesome I guess I don't know how they get that kind of compliance. And then before we forget the VF patients, they have fewer VF patients in this group, so only 75% of these patients had VF. So they're different cardiac arrests and we all know that a PEA arrest acts differently than a VF arrest right? Especially when they're in hospital cardiac arrest. Think about that, how many times you've wondered, Did that patient actually have an arrest it was a PEA arrest. I couldn't feel a pulse but the first person that came into the room could feel a pulse. Was there actually an arrest or not? There's a very fine line with PEA. And then also the median start time between arrest and the beginning of basic life support, one minute. This is a different group. It's not, it's not, it's not, our group. Right? It's not the patients that we see and when you're looking at a study and you're evaluating, should I bring this study into my practice, one of the first things that they teach us is you have to make sure that it's the right population, that the practice that you're thinking about starting or the study is performed on a population that's similar to your own population or practice setting that's similar to your own practice setting. This is not. This is not similar to really anything in the United States. And then they also got a median return spontaneous circulation about 25%. So that's actually, that's actually about that's doable in the US, we've seen that. Now what I've done here is we've got the temperature profiles now for HACA and Nielsen and I've lined up the temperatures here. So this is 32 degrees, that's 32 degrees that's 39 that's 39. Just to point out the profiles are very different for the control groups. This is the median temperature for the control group in the HACA trial and the median temperature for the control group for the Nielsen group. I see there's more than a degree of difference there. This is actually a good thing. So in the Nielsen study, they actually had a third party decide, make all the decisions on withdrawal of care. I'm assuming everyone industry has been involved in withdrawal of care decision making process at some point, playing a role either with the family members directly or in counseling the family members at bedside and it's a very tricky situation. Right? We do this I know at training hospitals something that we see is there's work avoidance, so when I was training there was a lot of work avoidance. People would counsel-- there's was this culture of despair and our residents right after getting an-- our ICU residents, right after getting an admission for a cardiac arrest would immediately initiate family discussions. Right? We need to have a family meeting. And I think it was driven by despair potentially and I hope, I hope not, but driven by this kind of work avoidance you know. They're overworked and so if they have one less patient it's less work. It's probably an unconscious kind of motivator, and it took several years to turn that culture of despair in to me getting paged at 3:00 am in the morning for every in hospital cardiac arrest even if they don't have ROSC they'll call me just to talk to me about their cardiac arrest and what we might do to save this patient. So that's completely turnaround. So the University of Chicago right now, is a very active program and we will advise teams to avoid these end of life sessions for at least 72 hours. Don't make these decisions right after grandma hits the ICU. OK I pointed this out already kind of lower rates of post ROSC shock, actually I didn't point this out, so in Nielsen these patients weren't quite as sick as they were in the HACA trial, which is interesting, and their STEMI rates were 49% in the Nielsen trial, which is higher than the HACA study potentially. So recently the international, this is the international body that kind of includes the American Heart Association, made an interim statement with this new data and they said, based on this new data here's our interim recommendation. They said you know what? Good outcomes, and this is typical of like a international body right that sounds like the UN. But good outcomes without excess risk are obtained with TTM at 33 degrees Celsius. OK statement of fact. TTM at 36 degrees has found similar good outcomes but formal evidence review is lacking. And that's true so there's really only been one study and there hasn't been kind of a lot of post HACA analysis yet. Pending a consensus on optimal temperature stay of course, my words not there's obviously they wouldn't say that but just keep doing what we're going keep cooling patients. But we will accept that some clinicians may do something else. OK may make some local decisions to use a target temperament management goal of 36 degrees, pending further guidance. OK so they basically said you can do whatever you want, but you got to do something OK you can't just let temperature roam free. All right so what does that mean then when we put it all together. So the way that I put this together and I held a couple journal clubs with my residents to try to air the data and knowing that I'm completely intellectually conflicted on this, right? I've been publishing papers on this stuff, I've been doing research for the last decade on hypothermia so I'm intellectually conflicted if this doesn't work, I don't have a career. Actually I don't really have a career. It doesn't look-- as it turns out it doesn't really matter. So with that freedom I also then took to the residents and said what do you guys think? And I talked to folks across the country at conferences to try to come up with a good policy at the University of Chicago. And so given that TTM trial didn't show any harm it was a neutral trial, The patients in this trial or possibly not as sick as the patient's not pocket trial over the Bernard trial is certainly not as sick as, they don't seem as sick as the patients that I see in my practice. And that we can't as practitioners, we can't tell who's sick and who isn't sick when they hit the door. They've all just died, they've all got ROSC. We have some hints maybe they've got some post resuscitation cardiac dysfunction, right many of these patients die within the first few hours. I've got kind of a funny story, I was moonlighting as a resident one time and I had a cardiac arrest and we got ROSC and I was all excited and we know what typically happens right? We all walk out of the room to do are charting and the patient kind of becomes hypotensive. That's typical and that's the intern sitting in the room. But in this particular case I asked for some Dobutamine to be started, and I was starting to charting and then the nurse said OK Dr. Beiser the Dobutamine is in. Anyway, there was no harm the patient did fine but that was a-- so it's going to have nurses that you know and you trust but I was moonlighting, I didn't know any of these nurses it was very different than kind of working in my home my home institution. All right so that's kind of irrelevant, but anyway we can't tell who's sick, ahead of time. So we have to make a decision. This is all evolving right in front of us. We've got mountains of pre-clinical data so that's animal data. So there's, people have been doing animal research on this in mice and dogs and sheep and pigs for decades. And it works in all of these models of cardiac arrest. We've got lots of META analyses, we've got two RCT's this should be protective. So what we've concluded is this most of our patients we're going to still cool them. OK? But the overriding kind of lesson for us is that everybody gets something. So it used to be that if a patient potentially was bleeding or they were making some end of life decisions, a patient might have metastatic disease or there might be some other reason why we wouldn't want to cool the patient. Perhaps they were hypotensive and we weren't certain that we would be able to support their cardiovascular system in the face of cooling. We just wouldn't do anything. I think the lesson of the TTM trial is that you have to do something. So every patient gets some type of TTM and that yeah a more flexible approach is reasonable. So it allows a little bit more on the ground kind of decision making. And so what we're doing we're also avoiding, as I mentioned it, withdrawal of care decisions for 72 hours. We do kind of post arrest, very aggressive management. How many people routinely send all of their cardiac arrest, all of their presumed, reword this very exactly, all cardiac arrest that are not obviously non cardiac to the cath lab? Right so the patient comes in, you get ROSC, do they go to cath lab? Do you have to see a STEMI to go to the cath lab? Which of you out there routinely send patients to the cath lab following ROSC? So this is interesting, thank you Ira. So at University of Chicago, unless you can prove to me that this patient is obviously, had an arrest for a non cardiac reason, right they're sitting in a pool of blood, they've got some obvious neuro deficit or something like that. The patient gets evaluated by the cath lab team and most of these patients wind up going to the cath lab. What they found is when you take these patients to the cath lab over 60% of them will have a culprit lesion. So this is a lesion that they can see in the cath lab that's responsible for the cardiac arrest. And the post ROSC EKG is not a very good way to screen for these patients so most of them don't have STEMI semi criteria on their EKG. So we'll call the cath lab -- all of our patients when they come in the cath lab gets alerted, and then they will check in they'll either come directly to the emergency department or they'll check in with the attending or the resident and get the story. And if there's a chance of this is cardiac they're going to the cath lab. They don't always get stents in fact they only stents maybe 30% of the time. But often they could use a new dynamic optimization in the cath lab, either putting in an impella pump or a balloon pump, something like that to help support the blood pressure in this patient for the first 24 to 48 hours. Occasionally they'll even put these patients on bypass.
