Dr. Sarah Nelson, a neurointensivist at the Mount Sinai Health System in New York City, discusses the current state of evidence surrounding targeted temperature management for patients with cardiac arrest, ischemic stroke, and brain hemorrhage.
find North therapeutics for uh for cardiac arrest and for some of the other diseases that all talk about. So, you know, particularly cardiac arrest, you have a global cessation of struggle, profusion followed by re profusion injury or injury if you're able to achieve Roscoe. And uh there's a variety of um subsequent down the line things that can occur um a variety of factors that get up regulated in particular out of um inflammatory um markers um and free radicals and so forth. Um And this becomes a little bit more relevant when you try to conceive of what could be going on when you apply hypothermia. In these cases. I'll be talking in the next few slides about some of the studies that have shown that its benefit and cardiac arrest and other illnesses, but why might this be the case? And so um there's some thoughts that um like for instance, you're reducing the glucose and oxygen requirement and so you're trying to help mitigate mitochondrial dysfunction and um in cases of cardiac arrest, you're helping to reduce free radical formation in these cases suppressing re profusion injury, increasing blood brain barrier permeability, as well as uh excited toxic injury that can occur with the uh with the coming of the brain with hypothermia. Trying to mitigate that as well as blocking the secretion of pro inflammatory cytokines and a variety of other um putative effects from applying hypothermia. So there's really three main stages to the application of therapeutic hypothermia. And they're pretty important in terms of wanting to follow them relatively exactly because of some of the effects that can occur if you if you don't and particularly rewarming phase. So um obviously the ideas obviously to induce it at some point and um I'll talk about there's uh not quite a uh exact temperature to which you can apply this to. There's different studies that suggest different uh temperature ranges. And we'll talk about that. There's also a variety of cooling devices and uh, the use of Colt sanely, which can also be used to apply Hypothermia as well. Those are continually evolving. And my plan was not to get into that too much today. Um obviously you want to maintain the uh therapeutic hypothermia for um, for a period of time, usually that's around 24 hours or more. Um, and as mentioned, there's various devices to help achieve that. And then, as mentioned upon rewarming, you generally want to do this in a controlled rather than a passive fashion. So instead of just kind of taking everything off and and calling it a day, it's generally a certain number of um, uh degree temperature increases in a very controlled fashion because of some of the ill effects that can occur if this is done to um, to quickly. So this is a slide that was done hard to believe 10 years ago but done in the New England Journal of Medicine where they were trying to demonstrate some of the potential cooling devices that could be used. But my plan was not to get into too much of that today. Um And uh just some of the human dynamic effects of when you apply hypothermia which can be um it's important to to keep in mind when you're deciding whether or not this is a therapy that you want to apply to your patient. So there's um you know you're generally kind of slowing things down so you can get bradycardia decreased cardiac output. Um You could get pr prolongation of QT prolongation. So some um E. K. G. Abnormalities. The uh figure on the left is demonstrating Osborne waves. Which is a feature you could see with hypothermia. And that's being demonstrated by these arrows here. With this uh basically this notch right after the curious complex. Um and interesting you can get this thing called cold viruses. Which basically means that because you're cooling the body. So so much the blood is being focused to the internal parts of the body which raises the blood pressure. And the kidneys correspond to that by um by diet racing out uh urine to try to try to compensate for that increase of pressure. Um So and then there's a variety of other electrolyte and um metabolite effects to uh to keep in mind. Um Susie could see here you really need to keep an eye on a variety of the electrolytes. Um potassium magnesium calcium phosphorus. Um and you can get a bit of a lactic acidosis as well when you induce it. So you know as I mentioned earlier, you want to rewarm in a controlled fashion because obviously there's a lot to uh lose in terms of cardiac and metabolic effects. If you were to go to quickly once bring the patient back up to a normal temperature. Some of the potential issue concerns also that when you cool people is um there is a increased risk of wound infections and of pneumonia. Kregel apathy is also concerned as well. So um including people who uh you know have known uh I. C. H. In addition to the other pathology that you might be considering to treat with hypothermia, you might want to reconsider or think more carefully about it because the quagga apathy the platelet inhibition in the uh in our prolongation that's going to occur as a result of applying hypothermia. Um Of course, another important thing is that when you uh slow your metabolism down, you're also slowing the metabolism down of all the drugs that you've administered to the patient. And so if you're trying to come up with a prognosis or do an exam or um something along that nature, you have to keep in mind. Of course that the drugs are going to take a lot longer to clear and what you're seeing on exam might not necessarily be uh the patient's fullest potential. Um And then there's a G. I. Effects as well, including um alias and um potential for increased LFTs. Of course, when you cool somebody as well, you um uh normal body's responses to shiver. And of course the reason why we shiver is to try to uh you know, bring our temperature back up to a normal range. Of course. That could be counterproductive to what you're trying to achieve when you're applying hypothermia. However, and there's a variety of medications that one could consider to give to patients, to try to help the treatment of uh shivering to try to not negate all you're trying to achieve by applying help with hermia, such as Tylenol abuse bar is a popular option. My parodying um some of the opioids, a bear hugger is a non pharmacologic option and sometimes paralytic SAR used as well. So, just I'm going to review some of the studies that have been done in some of the neuro critical care illnesses with a bit of a focus on cardiac arrest, because that's the disease for which we have the most data. Um The sentinel studies were done and published in the new England Journal of Medicine back in 2002, which it's hard to believe is almost 20 years ago, but um the two sector studies were released the same um, edition one was done by an Australian group and the other one was uh from the hypothermia after cardiac arrest group, also known as the Haka study. And both of these uh studies and teaches were to bring the temperature down to, as you can see here 30 to 34 degrees roughly. And both groups for either V fib or pulses via tech arrest. Um, and the cooling was done for 12 to 24 hours, depending on which uh study you're looking at. And the bottom line is that they saw that there was a notable better outcomes and decreased mortality. And those folks who got hypothermia versus those who did not. Um and particularly the in the hack of study, they had some nice diagrams to to demonstrate what they were able to achieve in this trial, which is on the right here. They were able to demonstrate that they were successfully able to achieve a temperature difference between the hypothermia and the folks who were left at normal author mia. And so they were able to achieve what they set out to do. And then when they performed the Kaplan Meier analysis there, there were subsequent able to demonstrate um a pretty stark difference here in mortality rates between the hypothermia and the normal hermia patients. I was the number needed to treat of of just six. And there were subsequent trials done to elucidate what could be the better temperature to place these patients at. This is one of the more famous studies that helped to elucidate that the T. T. M. Trial, which was published in 2013, which as you can see here for the title was uh Uh determining whether or not there were differences in outcomes between cooling 70-33°C vs 36. Um These were folks who sustain and out of hospital cardiac arrest. All initial um cardiac rhythms were included. Uh GCS had to be poor upon um Roscoe achievement and um the outcomes looked at survival, mortality and uh neurologic function. Um What they found in the studies that there was no difference in outcome between the two groups. As we could see here from the from the Kaplan Meier curve. Though it should be noted that as I was showing a couple slides ago, the Haka study performed in 2000 and two was able to achieve this nice um delineation between the hypothermia, normal throwing of people where and the T. T. M. Trial, that distinction was not entirely clear. So whether or not they were they actually um got the results of the study that they actually plan to do is um is not quite certain. But these days, there's um based on some of the this evidence that we have here, um it's still not entirely clear that what to what degree patients should be cooled. And this is just more on the outcomes from the same trial demonstrating no differences in mortality or neurologic function or serious adverse of ex uh if we're looking at that as well. Um when we're looking at uh in hospital cardiac arrest. So the all the pretty much all the trials that have been done um so far in cardiac arrests were done and out of hospital cardiac arrest. Um there's actually, as of now, still no randomized control data done on patients who arrested in the hospital. Um they, so this group in 2016 published a jam attempted to uh look at this by using propensity score analysis to try to match the patient as much as they um could. Obviously it's not the same as randomized trial. And interestingly, they found that therapeutic hypothermia was associated lower rates of favorable neurologic survival um uh than um than normal thermal to and this was true for both rhythm types here, referring to both non chocolate, which is a Sicilian P. A. And Shaka Bill, which is V. Fib and pulses feet tech. Again, not randomized control data. It was propensity score analysis but something interesting to think about. Um and then uh one of the other signature trials that just came out a couple years ago about um using therapeutic hypothermia was specifically focused on non shock double rhythm. So, the most of the previous trials I just discussed were specifically focused on V. Fib and pulses V. Tech. Um there really wasn't as much data on some of the non chocolate rhythms A. K. A. A. Sisterly pE. A. So this trial was designed to randomize patients to cardiac arrest patients to 33 degrees Celsius versus 37 degrees Celsius. And so these were all patients who are commentate toes in the ice you um after achieving ross like and um on day 90 they found that uh the better cbc cerebral performance category was achieved in those who were hypothermic versus those who are normal formwork which with the significant p value with no difference in adverse events. Um suggesting that there is some benefit to be had in um applying therapeutic hypothermia for non shock double rhythms, notably there was no difference in mortality in 90 days. However, what I did find interesting about this trial is when you look at some of the data, however similar to the T. T. M. Trial, I'm not sure that they achieved what they set out to want to achieve. Which um if you look at the differentiation and the and the temperatures that they were that they were going for. There's really actually no distinction between the hypothermia, normal hermia. Um Because you could see the 95% confidence intervals overlap. But um alas it was a randomized control trial and a topic that hadn't been previously studied before and um and was published in the new England Journal. Um So the american Heart Association and the american Academy of Neurology have both um based on these Charles have been done have kind of put out some guidelines for um us to you know potentially follow H. A. Has a pretty strong recommendation for using therapeutic hypothermia in all cardiac arrest survivals with survivors with no meaningful response to commands after Roscoe. And this is true for all rhythms and inside and outside the hospital where the A. N. Is not quite as ambitious and what they're recommending but still recommend uh to some degree therapeutic hypothermia for all types of rhythm types. Again though, the degree of hypothermia to which to place patients though is still not entirely clear. Um I didn't want to get too much into prognostication because I think this was discussed on previous um pearls. But um just as as a reminder though, this was kind of uh one of the signature papers that came out and um neurology related to cardiac arrest prognosis back in 2000 and six, which was before kind of uh therapeutic hypothermia became uh more or less the standard for treating um comatose cardiac arrest survivors. And uh by and large a lot of these markers that we're looking at here really have to be taken with a grain of salt or have to be waited to be evaluated upon. And those who got hypothermia because of the uh the potential to um uh prolonged drug clearance and so forth in order to get an accurate exam. And so there have been some cases for instance where uh patient was alleged to have reached brain death better than upon going to the operating room safe for organ procurement, regained some reflexes. So it's really critical in a lot of these cases to be able to assess these patients at uh date. Um right now it's postulated at least three days or so away from um from when the therapeutic hypothermia is applied. Um just briefly on third use of hypothermia in T. B. I. Which has also been evaluated in a couple of trials as well. This was a trial performed in uh 2001 Randomly assigning TB. I patients to hypothermia. 33° were normal hermia. Um and there was a poor outcome and 57% of patients in both groups with no difference in mortality concluding that there is um this treatment is not effective in improving outcomes course. There were some caveats in this trial which is that the when they were evaluating um uh you know uh which is uh I. C. P. And um treating it in in this trial. They weren't doing it necessarily in the ways that I think um other countries including our our own would uh normally treats such as with that. They started with the paralytic for instance rather than you know starting with what we might consider first line which is You know e. v. d. and um in a Mannitol and that sort of thing. And they also only maintained the cooling for 48 hours regardless of um I. c. p. Um there's another famous trial that was published in 2015 called the euro therm trial. Um and um whoops sorry guys I'm not sure what happened there. Um And basically they were also evaluating um I. C. P. Control um looking at Stage one treatments um which I'll define on the next slide. Um uh So they were looking at comparing those with standard care versus those of uh hypothermia plus standard care and um I'll talk about this on one of the next slides here but they kind of had a staged algorithm to which they were treating um I. C. P. And basically those who reached stage three treatments. Um uh There was basically no statistical difference there. Um And when they were evaluating the extended Glasgow outcome scale which is the gauss either abbreviation there, it turns out that they found worse outcomes in the in the hypothermia group. Um So uh in favorable outcomes uh um yeah worse than the in the hypothermia group. And so um what they concluded here is that hypothermia plus standard of character reduce I. C. P. Did not result in um and better outcomes which was which was interesting. Um However and as uh just further details of the trial here, the core temperature they were treating here. So again there's no um uh you know, definitive uh temperature which to cool these temperatures. So 30 to 35 is what they decided in this trial. Um and then as compared to the other Trial the cliff to trial done in 2001 this one they continued hypothermia for as long as it was necessary to control ICP. Especially though there were some caveats in this trial. For instance the once again the the staging of the treatments for I. C. P. Wasn't as I think um a lot of us would necessarily treat with for instance analgesia with without paralytic was considered a first line treatment. Whereas you have to kind of go all the way down to stage two before you're talking about hyper tonic sailing and mannitol. So there are some caveats with this with this trial as well. Um However based on the limited evidence that we do have based on these trials and a couple others on in T. B. I. Um the uh the american College of Surgeons best practice guidelines is what's the brain trauma foundation um says that they do not recommend prophylactic uh therapeutic hypothermia at least in the case of brain trauma foundation or unless other treatments have have failed to elicit um I. C. P. Control. Um interestingly uh just to know about hypothermia and an ischemic stroke. There have actually been some studies done on all of these patients generally. These are patients with pretty high stroke scales and all of most of these are feasibility studies and weren't really designed actually to um try to uh tease out whether or not a difference like this is a very small study here of only of only 19 patients. Um So they did one uh interestingly called Kool Aid and then there's Kool Aid to some cute names I suppose. So um this one in particular Kool Aid to especially focused on interest circulation strokes. And they also looked at wi leisure growth for which there was no difference. But the bottom line is some of these studies have shown that this is um feasible and acute ischemic stroke again wasn't power though to show any differences. Um and really didn't show any difference in um adverse events either though. And these are just a couple of the other um studies that were done here. So to summarize these data, the american heart association has stated that Given the lack of evidence no no trial with class one evidence so no like formalized randomized control trials. Um there or or a sufficient sample sizes dimensionally 11 of the studies had only 19 patients. Um there really is no uh guidance they can provide on this at this time. Um shivering was an issue in some of these trials. There are some issues with the um with the application of hypothermia and obviously to be concerned about is the rewarming phase and rebound I. C. P. And other issues like that. Um So status epileptic is also they there has been um some some data out there. I would say that the probably the biggest Charles to date and the one that is um the most rigorously done because it was done in an a randomized controlled fashion. Was this study that was published in the Journal of Medicine in 2016. These were convulsive status epileptic as patients who were intubated randomized to hypothermia plus a standard of care versus standard care alone. And looking at the Glasgow outcome scale of five at 90 days. It was similar in both groups uh with a non significant p value. Though interestingly the rate of progression to status epileptic ast confirmed on the E. G. In the first day. Um It turns it was less uh less so in the group who got hypothermia versus a control group. So some some food for thought there and what what could be going on there. Um And there were some more adverse events going on in the uh that occurred in the hypothermia group. Um And then uh lastly um shh and I ch there's really not much data out there at this time. Uh Not any randomized control trials and either one that have been published anyway. Um So an S. H. In particular it doesn't look like at least from what I could see that there is anything that's ongoing or um has been published uh in the field of I. C. H. However um there are two currently ongoing trials that are designed to evaluate whether or not hypothermia is beneficial in this um in this disease. So um I think it would be interesting to see given what I was saying earlier about cuadrilla apathy and the use of hypothermia what might actually occur when this is applied in a systematic fashion? Yeah. And that's all I had to share today. Mhm. Mhm. If we were going to apply this in uh interesting hemorrhage. Do you from the data? Can you make a recommendation about what temperature would be safe with the Hippocratic hippo collectibility issue? Yeah. I mean I would think that given the concerns of quagga ability and the fact that there really isn't a um like a definitive temperature out there uh that's um known to uh Definitively um be the temperature at which you apply therapeutic hypothermia. I mean I think 36° would be a safe bet at least to start and see how how patients do with that. So chris and the Endovascular team it would seem that endovascular therapeutics and interventions would be an ideal place to apply this. There have been there are devices um what do you see as the role for hypothermia in endovascular therapeutics? Or in the Endovascular World? I'm aware of a few efforts to perform intra procedural um cooling during thrown back to me and even uh started initiated during thrown back to me and start And continue it for six hours afterwards. Um Yeah there there's one there's one ongoing trial to do systemic cooling. Um And then there's another that I'm not aware of any details about but for doing cooling. Intra arterial intracranial cooling um from the guide catheter during the procedure, but I'm not sure how that is maintained afterwards. It does seem to me like there is quite a bit of potential there. Um Some animal research suggests that cooling could also help decrease some of the re perfusion injury that might happen with throw it back to me. And so there might be an advantage to initiating the cooling prior to throw it back to me or or at the beginning of the procedure. I see Cappy raised his hand here so I'm gonna him up Happy. The other comment just really just quick. I was just gonna say, you know, I think one of the limitations with cooling in the setting that you described is is you know, in order to effectively cool, you really have to sedate these patients. They don't tolerate the cooling very well and then you lose the exam. Um And I think that's figuring out a way to maintain a neurologic exam while you're applying therapeutic hypothermia. Is is a challenge. There are many challenges. You know, for for endovascular for vascular you want to cool the part of the brain that's not being confused. Right? And so an infusion of cold or killed liquids or or cooling the blood can only get to the penumbra that's being confused. So that's that's a problem. And you know, Sarah very nicely outlined it. Um How dangerous this can be. My experience here at santa. In cooling occurred when we were doing the cardiac standstill cases in the days of um total circulatory arrest For treatment of unclip. A ble giant aneurysms. We did a few. I have one picture that I should have brought today that shows a median stern ah to me and a craniotomy at the same time. Um Which is how we used to do it. That's maximally invasive. Most maximum invasive surgery you can imagine. And in order to get 60 minutes of circ arrest. You know, we could go to 60 minutes of circulatory arrest. We had to cool down into the low 30's like 32. Um which wreaks havoc on the coagulation system of the patient that blood just doesn't clot. Yeah, so we had a really, really serious problems and warming these patients up. As Sarah also mentioned that the way that you get them back is as important as the ways you get them down. Um it would be interesting to see it clearly. It works, but it just shows how connected the brain is to the rest of the body. She's very hard to do it in isolation.