»» Thank you so much, Caitlin, for the kind introduction. Just a small correction. I am not in the Executive Committee of Neurocritical Care Society, just the Curing Coma Campaign. So with that, we'll get started. So the topic for this session is Targeted Temperature Management Post-Cardiac Arrest. And my stand is that it is pointless. So Caitlin's already gone over my introduction. I have no relevant disclosures for this talk. The learning objectives for today's talk is we're going to review the evidence for Targeted Temperature Management. We're going to review evidence against Targeted Temperature Management. And we're going to synthesize the data we have to date to understand what's the right way to practice. So let's get started with how does temperature regulation work? So in order to maintain your temperature at a steady state, you would have to match your heat production with your heat loss. And what are the factors that affect your heat production? Of course, your metabolic rate, which is basically every time you have ATP generation, the process of electron transport and oxidative phosphorylation is converted to heat. Every time you break down protein, carbohydrates, and fat, you generate heat. So we have to match that with heat loss. How does that occur? Well, you have to increase the blood flow to the region of the tissue. In this talk, we're talking about brain tissue in particular. So that helps dissipate the heat. And the other factor would be the temperature of the blood that's flowing through the tissue. The cooler the temperature, the increased heat loss. Now let's pause for a second and think about how does Targeted Temperature Management come into play in this equation of heat production and heat loss? So it reduces heat production by decreasing your metabolic rate and decreasing your cerebral metabolic rate of oxygen consumption. In terms of heat loss, it does reduce your temperature of the flowing blood across the brain tissue. However, we have data from animal models showing that actually cooling or induced hypothermia reduces your cerebral blood flow proportionate to the degree of reduction in cerebral metabolic rate or metabolic rate. So here we have one, reduction of metabolic rate, two, reduction in temperature of blood flowing through the brain tissue. But counteractive to that, it also reduces blood flow flowing through the tissue. So I want you to think about that for a second as we go through this talk. So what are some of the reported effects of therapeutic hypothermia, largely based on animal studies? And the human studies that really started looking at the benefits started in 2002. But most of the animal studies suggested induced hypothermia decreases your cerebral metabolic rate of oxygen consumption, thereby preserving your neurovascular coupling and preventing ischemia. It reduces your oxidative stress, reduces excitotoxicity, reduces complement activation. The subsequent autophagy apoptosis is also reduced in induced hypothermia. There is also animal evidence to suggest decrease in blood-brain barrier leakage and decrease in cerebral edema. What about human studies? So the primary initial evidence for targeted temperature management in humans, the big trials that came out that changed our practice was in 2002. Both of these studies came out in 2002. The first one, the Bernhard et al. study, it basically looked at 77 patients, an Australian study where they cooled the patient to 32 degrees within two hours of attaining ROSC compared to a control group of normothermia. And they only included patients with shockable rhythm out of hospital cardiac arrest, which is VTAC, VFib. And they concluded that moderate hypothermia to 32 degree appears to improve outcome at discharge in patients with coma after out of hospital cardiac arrest. The same year, the European group, the HACA group, published the study where they looked at 275 patients, again, shockable rhythm, VTAC, or VFib. And they randomized the patient to hypothermia, which was 32 to 34 degrees versus normothermia. And the investigators concluded that therapeutic hypothermia increased the rate of favorable neurologic outcome at six months and reduced mortality. That really brought us to this practice of induced hypothermia in our post-arrest patients, primarily in patients with shockable rhythm. But then, here we have, in 2013, Nielsen and colleagues looked at patients out of hospital cardiac arrest patients. They evaluated 950 patients and included 939 patients in their primary analysis. They included all comers, not just shockable rhythm, but included the non-shockable rhythm as well. They only included patients with asystole who were technically found down, so we really don't know how long that was going on for. And they randomized the patients to 33 degrees versus 36 degrees. And they found, in unconscious survivors of out-of-hospital cardiac arrest of presumed cardiac cause, hypothermia at targeted temperature of 33 degrees did not confer benefit as compared to targeted temperature of 36 degrees. And they evaluated their outcome was really 90-day all-cause mortality and 180-day mortality as well as functional outcome. So, that was a little bit of an interesting trial when everyone had started practicing hypothermia. So, what were some of the reasons the trial findings could have been different? People started thinking about it, writing about it. Some of the main differences pointed out between the trials were, in the earlier Bernard and Haka trials, there was lack of adequate temperature control in the control group. The control group had average temperature that was over 37 degrees centigrade, so maybe, because their control group wasn't well-controlled for fever, maybe they had poor outcome, whereas in Nielsen's group, there was tight temperature control in 36 degrees centigrade control group. Also, in the earlier Australian and European trials, the neuroprognosticator was unblinded. They knew whether it was treatment or control group, so could that have affected how they assessed the outcome? As opposed to Nielsen's study, where there was blinded neurological prognosticator. In addition, this is an important factor, there were lower rates of bystander CPR in the earlier trials, only about 43 to 49 percent, compared to much higher rate, about 73 percent of bystander CPR. So, people are like, okay, maybe, you know, patients had baseline poor care back 20 years ago, and maybe we're doing better over the years, and maybe that's why we don't really see a difference. But here, after the 2013 Nielsen study showing no benefit, this study, the Hyperion trial, was published in 2019 in NEJM. And here, the investigators looked at out-of-hospital cardiac arrest patients with non-shockable rhythm, and randomized them to 33 degree for 24 hours, compared to targeted normothermia, which they called as 37 degrees, and assessed a 90-day outcome, functional outcome that CPC scores, and what they found, they looked at a total of 584 patients, and included 581 patients in their primary analysis. What they found was, among patients with coma who had been resuscitated from cardiac arrest with non-shockable rhythm, moderate therapeutic hypothermia to 33 degrees for 24 hours actually had a higher percentage of patients who survived with a favorable neurologic outcome at 90 days, compared to targeted normothermia. Well, that's more confusing. So we've said hypothermia is great, and the 2013 study, all comers, shockable, non-shockable, maybe hypothermia doesn't really matter to 33 degrees. And then here's this trial including the non-shockable rhythm patients that says, oh, hypothermia is probably good for these patients to improve functional outcome. So based on all these studies, the 2020 American Heart Association Guideline for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care came up with these recommendations, with the caveat that at this point, they were awaiting the results of the TTM2 trial, which was published later in 2021. At the time, they said, on the left-hand side, the first two columns, the first column is a class of recommendation, and the second column is level of evidence. You can see the top recommendation is a class one recommendation based on randomized control trials. And they said, we recommend selecting and maintaining a constant temperature between 32 to 36 degrees centigrade during targeted temperature management. They said it is reasonable that targeted temperature management be maintained for at least 24 hours after achieving targeted temperature. And lastly, they said it may be reasonable to actively prevent fever in comatose patients after targeted temperature management based on limited data. Then here comes 2021, where the TTM2 trial was published. And here, they looked at 1850 comatose patients suffering from out-of-hospital cardiac arrest, and they randomized these patients to 33 degrees for 28 hours, followed by re-warming back to 37 degrees, and compared them to people with normal thermia, which they considered anyone less than 37.8. So they started early treatment of fever if anyone had approached closer to 37.8 or higher. And this group found that targeted hypothermia did not lead to a lower incident of death by six months than targeted normal thermia. And there was really no difference in survival with severe neurological disability, which they defined as modified Rankin scale greater or equal to four. However, they did notice that patients in the cooling group, the targeted hypothermia group, had increased rate of arrhythmia that resulted in hemodynamic compromise compared to the normal group. So what are some of the comments that have been made regarding the difference in results of all these trials? People have said, you know, maybe 20 years back, our standard of care was bad. So the control group did naturally bad, as opposed to a very other trial group. So maybe that's what's diminishing the gap between the patient and control groups. There's been a lot of meta-analysis looking at selection bias of the patient, you know, timing of rust, how long they were down, things like that. There's delay in implementation of cooling protocol have been found in several of these trials in the treatment group. There's also been poor management of temperature in the control group. The original HACA and BRNR trial, interestingly, they control average temperature in the control group was actually greater than 37 degrees, as opposed to newer trials, which maintain normothermia in the control group. And no one really knows the effect of sedation and analgesia because people were free to do whatever they want, put them on however much propofol or sedation analgesia they wanted to know. So we haven't truly understood the effect of these medications that is needed to keep patients hypothermic. And again, the important confounder which happens very commonly in this group of patients is early withdrawal of life-supporting therapy which could have affected the mortality outcome. So now we've looked through some of the trials that has evidence for and some against, let's kind of synthesize the data we have against targeted temperature management. So let's look at this 2013 study by Nielsen we already talked about, 33 versus 36, no benefit of 33 degree in out-of-hospital cardiac arrest patients regardless of whatever rhythm they had at presentation. The 2021 TTM-2 trial, really almost 1850 patient evaluated, 33 degree versus normothermia did not lead to any lower incidence of death by six month compared to normothermia. And again, there was also this large registry about 1145 patients with non-shockable rhythm that compared 32 to 34 degree centigrade targeted hypothermia to normothermia group and they also found that therapeutic hypothermia is not associated with good outcome. So is that all the evidence we got? Not really, there's been plethora of evidence, multiple other studies that has looked into this. And I don't intend to go into each of these studies, but these are the studies between 2015 to 2020 and in a resounding manner, all of these studies, whether it's 33 versus 36 cooling for 24 hours versus 48 hours, early cooling by starting cooling in the pre-hospital setting versus delayed cooling in the in-hospital setting, none of this, these trials suggested there's increased benefit of either survival or functional outcome. So with all this data, people were able to do the systematic review and meta-analysis. This group by Fernando and colleagues looked at about 10 randomized control trials, including about 4,218 patients and they looked at people who had moderate hypothermia, or mild hypothermia, moderate hypothermia and deep hypothermia, deep they define as 31 to 32, moderate 32 to 34 and mild 35 to 36 degree and compared that with a normothermic patient and they synthesized all the existing data and they basically concluded that mild, moderate or deep hypothermia may not improve survival or a functional outcome after out-of-hospital cardiac arrest as compared to normal thermia. However, moderate and deep hypothermia were associated with higher incidence of arrhythmia as also noted in TTM2 trial. So that was not just it, there's been several systematic review. This is from the International Liaison Committee on Resuscitation Advanced Life Support Task Force, which basically reviewed about 32 different trials and they came with very similar conclusion. They looked at targeted temperature management 32 to 34 degree versus normal thermia and they came to the conclusion that adult patients with cardiac arrest, the use of targeted temperature management at 32 to 34 degree when compared to normal thermia do not result in improved outcomes based on this analysis. So based on, okay, before we get there, okay, so targeted temperature management so far based on multiple studies, based on systematic review and meta-analyses do not seem to have significant benefit on these patients. But what about fever control? Is there any harm of letting patients not being managed and just letting them have fever? In fact, yes, there could be harm. First of all, how common is fever in this cardiac arrest population? Fever is quite common in up to 42% of these patients and we do have evidence suggesting poor survival in post-cardiac arrest patients when the temperature was equal to or above 37.8, which is why there's recommendation from AHA and I'm gonna shortly talk about ESICM recommendation. And fever is also associated with increased inflammatory cytokines and subsequent pathways that leads to brain injury. So with that, synthesizing all the available evidence that we have, the most recent 2022 ESCIM guidelines, the recommendation for temperature control after cardiac arrest in adults is right here. And it reads, it recommends continuous monitoring of core temperature in patients who remain comatose after ROS from cardiac arrest. Yes, we wanna monitor temperature because fever may be bad. It recommends active treatment if the temperature goes above 37.7 degrees centigrade. So we wanna keep the brain less than 37.8 degrees centigrade. This guideline recommends fever prevention for at least 72 hours post-cardiac arrest. And you can use any cooling method, whether you wanna use just exposure to cold, antipyretic drugs, and if that's not enough, you can use cooling device to maintain 37.5 degrees centigrade in these patients. And it basically synthesized the data and says there's really insufficient evidence to recommend for or against cooling patients to 32 to 36 degrees centigrade in subpopulations. It doesn't say all comers. It's talking about subpopulation of, because there are some populations, maybe severe brain injury. Some of the trials with severe brain injury patients seem to have benefited from lower temperatures. So in subpopulation of cardiac arrest patient or using early cooling, and future research may help elucidate this. And we have the iSCAP study coming up and hopefully it'll help us give us some answers. And lastly, it recommends not using pre-hospital cooling with rapid infusion of large volumes of cold IV fluid immediately after ROSC, because that has been shown to increase your risk of re-arrest and increase the risk of pulmonary edema. So if you were one of those people who are like, I don't care what the evidence says, I've been cooling people after post-arrest forever, and it works for my patients, I've seen better outcomes. I want you to pause for a second and think about what could be potential adverse events of cooling. We've seen from the trials and meta-analysis increased risk of arrhythmia. There are studies reporting increased risk of pneumonia in these patients. Patients who are cooler tend to bleed more. So if you already have coagulopathic patient, probably not a great idea to cool them or if it's not strongly indicated. I already talked about the high risk of re-arrest and pulmonary edema, especially with rapid infusion of cold fluid, which was a trial done in pre-hospital setting. And again, like cooling these patients intensely is nursing intensive. They need intensive monitoring. They need increased sedation. They need anti-seizure management somewhere between 34, 35.5 degrees centigrade. They tend to shiver the most. And we really don't know the side effect of these additional sedation and anti-shivering regimen that we've put on these patients. And for those, once they're out of the cooling, there's always risk of rebound pyrexia. And let's also think about the cost. If we don't have strong evidence to show benefit in mortality or functional outcome, we probably don't wanna spend a whole lot of dollars in something that's possibly futile. So with that, I wanna bring your attention back to this slide again. We talked about temperature regulation is the equation between heat production and heat loss. And again, we talked about how does hypothermia help temperature regulation? One, it reduces brain metabolism. Number two, it decreases the temperature of blood flowing through the brain tissue. However, instead of increasing cerebral blood flow, which is helpful in reducing heat or taking away heat, it decreases blood flow. So what we really wanna understand is, is temperature regulation truly, what is, which of these equations induce hypothermia is most active in? Are there certain population that benefit from targeted temperature management as opposed to other population? And we'll talk about in a brief moment, but before that, let's quickly review this very interesting study published in 2022 in Brain. It says, a daily temperature rhythm in the human brain predicts survival after brain injury. Interesting, right? We all know here, we monitor where people in the ICU, we monitor body temperature throughout the day. We know there's daily variation to body temperature. We also, studies have shown, and some of us may have had personal experiences when we place brain monitors, that there is daily variation of temperature in the brain as well. In fact, not just daily variation, but it also varies by region in the brain. The deeper brain tissues have lesser blood flow, so their temperature tends to be a little higher than the cortices that tends to have a higher blood flow. So this retrospective study from the Center TBI group looked at 114 patients. They included 100 patients in analysis. They identified two things. Number one, they identified the daily temperature rhythm is affected in severe brain injury patients. They don't normally have temperature variability as normal people do. They used healthy volunteers as control, 20 males and 20 females, which had nice daily variation in rhythm. And interestingly, what they found is temperature rhythm, decrease in the temperature rhythm, actually, or lack of daily variation in the temperature rhythm increases the odd of death in intensive care by 21 fold. It does not matter what your high temperature or low temperature actually was. So it's not really the target, but the daily variation is what the study found, which is really interesting mixed into the data we already have so far. So I hope so far I've convinced you that the one size fits all approach of targeted temperature management to 32 to 36 degree post-cardiac arrest is really pointless. And maybe it is time we truly understand the pathophysiology of brain and identify the subpopulation that may benefit most from strict temperature control. Maybe the patient with severe brain edema that already is suffering from low blood flow or the patients with severely impaired autoregulation that's already lowering from cerebral blood flow, already suffering from that, may not be the ones who will improve with that approach. But how do we know that? How do we know which patients truly improve? We're so focused on shockable rhythm, non-shockable rhythm. The common pathway to both those rhythm is really just reduced cerebral perfusion, brain ischemia. Probably we should move away from that and really understand what's happening in the brain. One of the ways of doing that is monitoring what's going on in the brain, whether invasively, non-invasively. And I would go as far as saying, maybe it's time we start doing that. Maybe we should start monitoring these patients and really have a goal-directed approach therapy in managing our post-cardiac arrest patients. With that, I rest my case. Thank you.

targeted temperature management

post-cardiac arrest

evidence

temperature regulation

therapeutic hypothermia

neurovascular coupling