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Local to Systemic Use of Hypothermia

2018; Mary Ann Liebert, Inc.; Volume: 8; Issue: 1 Linguagem: Inglês

10.1089/ther.2018.29041.mjk

2153-7933

Michael C. Kurz, Patrick D. Lyden, Justin Lundbye, Suhrud M. Rajguru,

Traumatic Brain Injury and Neurovascular Disturbances

Therapeutic Hypothermia and Temperature ManagementVol. 8, No. 1 Expert Panel DiscussionsFree AccessLocal to Systemic Use of HypothermiaMichael Kurz, Patrick Lyden, Justin Lundbye, and Suhrud RajguruMichael KurzDepartment of Emergency Medicine, University of Alabama at Birmingham, Birmingham, Alabama.Search for more papers by this author, Patrick LydenDepartment of Neurology, Cedars-Sinai Medical Center, Los Angeles, California.Search for more papers by this author, Justin LundbyeChief Medical Officer, The Greater Waterbury Health Network, Waterbury, Connecticut.Search for more papers by this author, and Suhrud RajguruDepartments of Biomedical Engineering and Otolaryngology, University of Miami Miller School of Medicine, Miami, Florida.Search for more papers by this authorPublished Online:1 Mar 2018https://doi.org/10.1089/ther.2018.29041.mjkAboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail During the 2017 Chilling at the Beach Annual Meeting in Miami, an Expert Panel Discussion was conducted on the use of local or systemic therapeutic hypothermia in several clinical conditions. Dr. Patrick Lyden, Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, discussed the future of targeted temperature management in ischemic stroke and discussed an interesting approach including a stepwise method to optimize therapeutic hypothermia in recent preclinical studies. Dr. Justin Lundbye, Chief Medical Officer, The Greater Waterbury Health Network, Waterbury, CT, discussed the important concept of time to cool and the possibility of utilizing intracardiac arrest cooling strategies to enhance the beneficial effects of this treatment protocol. Finally, Dr. Suhrud Rajguru, Departments of Biomedical Engineering and Otolaryngology, University of Miami Miller School of Medicine, Miami, FL, talked about localized therapeutic hypothermia to preserve residual hearing after cochlear implantation. Dr. Rajguru discussed the concept of selectively cooling the inner ear to protect hair cells from traumatic injury and improvement in hearing. Together these presentations were followed by a question and answer session providing new information to the attendees of the meeting.Question:What is the relevance of those changes you saw clinically with someone with a cochlear implant?Dr. Suhrud Rajguru: Current Food and Drug Administration (FDA) guidelines permit cochlear implantation in patients of age 2 years and above with severe-to-profound deafness. As cochlear implant devices are continually improving, the criterion regarding the degree of hearing loss continues to evolve, and patients who have residual hearing at low frequencies, especially in children in whom it is difficult to evaluate, are being implanted now. After cochlear implantation, there is significant residual hearing loss in the implanted ear. It is a significant population that can be positively impacted if hypothermia can be used during the implant to help protect residual hearing among these patients. This also includes older patients who cannot use a hearing aid anymore but they still have some residual hearing at low frequencies but they have poor speech word recognition. Now with the revised FDA criterion, more patients will be candidates for cochlear implants.Comment: This is an example of how scientist and clinicians can get together to study a problem. I was giving a lecture to otolaryngology, and after the talk, I was asked whether I thought cooling would work in cochlear implants. I asked what are you talking about? I thought the cochlear implants were a big success story, but it turned out that the actual implantation of the implant produces trauma. The use of hypothermia in the implant now is producing some excellent results.Question:So, you hinted that you have looked at neurons, astrocytes, and pericytes, have you looked at any other cells in the neurovascular unit or even fibroblast that have been shown now to infiltrate after stroke and cause scar formation so maybe hypothermia would inhibit that resulting in a better outcome?Dr. Patrick Lyden: That is a great question and the answer is no. We have not done conditioned media transfer for any other cell type. Other laboratories have looked at transplanting microglia and there are protective phenotypes and toxic phenotypes of microglia and no one has done the hypothermia part of that either. We have a lot of things to do because I think the astrocytes are probably most important but I could not tell you for sure without actually doing the test for endothelial cells and pericytes. The ischemia tolerance is longest for astrocytes. They last the longest after oxygen–glucose deprivation and endothelial cells are intermediate. That is the opposite of what traditional pathology and selective vulnerability have informed us. If you look at the intact brain, endothelial cells survive the longest because they are closest to the heart. If you take all of the cells out and put them in dishes, astrocytes are the most tolerant.Comment: Just to follow-up, in some of your later slides, you used tetrazolium chloride (TTC) to actually outline the infarct area. The survival time for those animals was how long after the stroke?Dr. Patrick Lyden: In that model, the sacrifice and TTC staining was done 24 hours after a 2-hour middle cerebral artery occlusion (MCAO).Comment: So it will be interesting in the future to let the animals live longer to make sure that protection is sustained and results in some behavioral improvement. Those experiments are big and complicated but would be really great to do in the future.Dr. Patrick Lyden: That is a great point for those of you who do not do this sort of work, it is real easy to do TTC and you can generate data really fast, but there is not always a long-term benefit when you wait 3 months and do the behavior then and classical histology, sometimes those results do not hold true over the longer period. We want to do such an experiment, but because that experiment is so large and expensive, we need to get all the details ironed out and then do the definitive experiment.Dr. Michael Kurz: Dr. Lundbye, I have a question. You spoke at length about time to target temperature and how quicker target acquisition would be advantageous. This seems counterintuitive to clinical experience of patients who are more relatively intact who shiver or have higher metabolic output slowing their progress. Does this account for the difference between the preclinical investigations you showed us and clinical work that does not quite bear out or is there another reason for the discordance?Dr. Justin Lundbye: I think the benefit of the animal studies is that they are so controlled and something we do not have the luxury of in human studies. We are making a lot of assumptions, since every patient comes with a little bit of different clinical and physiologic background, comorbidity and other things can confound the whole process for the human studies. I do not think I would necessarily make that comparison, I just think it is nice to see these results in the animal study come true, but how we can apply that information to humans remains to be seen.Dr. Michael Kurz: That is exactly how I see this discordance between animal and human studies. Getting to target rapidly seems to be better; however, we want to see patients whose temperature curve is a bit shallower as they fight acquisition and may indicate they may be more intact.Dr. Justin Lundbye: So, theoretically if you can neuroblock these patients and get them down very quickly, perhaps there will be another message or another signal of better outcome because you have taken away all of the shivering mechanism.Question:When we think about patients who got hypothermia at the same time that they had their traumatic brain injury, these patients appear to have a better outcome than patients who are being treated with hypothermia much later and that plays exactly into what you were telling us about that the shorter the period of time that you get the patient to target temperature, the better the outcome. I remember the example of a Norwegian girl who fell into a creek and drowned and it took the rescue forces more than 30 minutes to get her out, and this patient although drowned, since she was cooled immediately, she survived without neurologic issues. There are several of these case reports that have shown that the immediate cooling at the time of injury seems to improve outcome. This is similar to what you were saying that we should cool the patients as fast and soon as we can.Dr. Patrick Lyden: I think those cases are emblematic of what we think works and why we think it works but of course getting that to be reproducible with all patients is the trick that has been befuddling us.Question:I was interested in the staircase method. There was no unit on the X-axis. How many hours do you do the different temperatures and what would you suggest if this should be transferred to patients, how many hours and do you think it would be possible to do in patients, to take them up and down that fast?Dr. Patrick Lyden: There are no units on the X-axis because we have no idea about minutes, hours, or days, so for now it is a hypothesis. It is a framework for thinking about next step experiments. Obviously, a predicate to doing a staircase is having a device that is powerful enough to get the patient from one temperature to another the way we do in the rats, so we are assuming that the technology will catch up. I did not make a point of it but I drew in dotted red lines there at the last version of it to indicate that there will always be some ramps. There will never be instantaneous changes and how much of a slope you put in is another question to be answered. As I said, it may not be two steps or three steps but maybe a ramp, but I think we have to think about what we do. Why do we have a ramp rewarm, why do we do that? Well, in a couple of studies, a stroke study and a cardiac arrest study when patients were rewarmed quickly without any temperature control, there were a few cases of overshoot, ICP rebound, and death, so we came up with the so-called ramp rewarm to avoid that overshoot. That is not based on a lot of science, it is based on a few studies wherein there was some bad outcomes, but with ramp rewarming, we did not see that anymore, but it does not mean that is what we have to do and it certainly does not mean that if you cool ultrashort that you need a prolonged rewarm. I think the prolonged rewarm is because they cooled so, 24–48 hours, they got themselves into the edema phase. If you kept the hypothermia to the neuroprotection phase, you should avoid that problem.Dr. Michael Kurz: I think that question and Dr. Lyden's answer highlight how little we know about targeted temperature management. How long to cool? How fast to rewarm? These and other questions regarding the application of targeted temperature management suggest that beyond Dr. Lyden's work, we have few answers. Where we do have data, it often conflicts between preclinical and clinical experiences.Dr. Patrick Lyden: To hyperillustrate the point, everybody when you get home on Monday, talk to the first neurointensivist that you see and tell the neurointensivist that next time we do hypothermia, we are not going to ramp rewarm, we are just going to warm right back up. They will tell you that we have to do a ramp, but try telling that to someone who has been trained that you have to have a ramp rewarm, and they will not believe you.Question:For Dr. Rajguru, why chose only 32°C because since you are not doing whole body cooling you could go as low as 1°C? For Dr. Lundbye, a recent article came out wherein they segregated the times from initiation to time to goal temperature, just curious to know your thoughts on that article? For Dr. Lyden, with the current equipoise that exists or the disagreement that exists, what is to stop us from doing clinical trials now where we pick three of the variables of interest in the staircase model and do an adaptive design that may more efficiently get to some interesting answers rather than the historical model wherein we are just doing two temperatures?Dr. Suhrud Rajguru: What I did not show were some of the data collected at different temperatures. So, we did several animals wherein we cooled down to 28°C and others down to only near 35°C. What we found was the range for protection of hair cells function happened to be between 30°C and 33°C. If you go <30°C, we did not get significant benefits. I do not know why that is, I am assuming that we are turning on some other mechanisms that might reduce the neuroprotective benefit of hypothermia.Dr. Justin Lundbye: I have not reviewed the study, so I cannot answer the question at this time.Dr. Patrick Lyden: In terms of an adaptive design, depth, target depth, delay, and duration, I think it is a brilliant idea. When I wrote that grant 15 years ago and approached National Institutes of Health (NIH) and Invasive Versus Conservative Treatment in Unstable Coronary Syndromes (ICTUS) was supposed to be exactly this, we had two different depths, two or three different durations, we would revise the protocol as time went by. The study section absolutely refused to fund the study on the basis that we need to know whether hypothermia worked. So, I made a mistake when I rewrote the grant in an attempt to do that, I had to make those decisions in terms of temperature chosen, delay, and duration. You have to win on all three with very little data to back up any of those decisions. The theory was that we would show some benefit with the parameters that I chose and then go back and do the comparison study for these parameters. However, we blew up on the launch pad and did not get to where we wanted to go and now we are stuck with a bunch of negative trials, and that is why I am doing what I am doing now. Going back to the laboratory and looking at all of this, depth, duration, and delay and figure out a way to rejuvenate the clinical trials and do them again.Question:After three brilliant but different talks, my take-home message was one of that we have to get temperature down quickly close to when the injury is. Is anyone on the panel aware of cardiac arrest trials that are about to adhere to that notion, that one ultrafast cooling will be done on the pavement and at the catheterization laboratory because then in Europe the TTM2 trial that we are going to part of makes no mention of rapidity of cooling and is obsessed with 33°C and the prevention of fever that one would imagine if they do not change the speed of cooling, then this will be another very big, very well-controlled conducted negative trial. Is anyone aware of a trial that is attentive to the speed of cooling?Dr. Justin Lundbye: I am not. I do think it is something that we need to think about.Dr. Michael Kurz: I think we are limited by the current technology. From an engineering perspective, it is a fairly simple physics equation; however, if we cannot push any harder, that is, rapidly deliver a larger heat sink, these questions will continue to allude us.Question:Two questions. The first one has to do with time to cooling and that sometimes patients who get cooled faster have worse outcomes and that sometimes this is the result of a sign of their underlying injury. I am a trauma surgeon and when patients are in shock, they are also cold just producing less heat. So, one of the slides that was shown looked at the number of degrees and how quickly you drop temperature and that was shown to be protective. That gets me the idea that not time to target temperature because if you start low you are going to get to your target quicker but what about just starting temperature, what is the prognostic value of that in general because if you come out of a cardiac arrest at a lower temperature, is that in and of itself a sign, that is a prognostic not just how quickly you get colder from there, and the second question unrelated is that with rewarming how much do we know about the effects on other body systems, but if you were to rewarm somebody, what does the literature tell us so far about other organ systems and how we need to protect them or not?Dr. Justin Lundbye: So, it turns out that starting out at a lower temperature is a poor prognostication marker like you alluded to. One of my first slides showed that despite that, the faster you cool does not necessarily better or worsen the outcome. In other words, the limited data that were there starting at a lower temperature does not change that. I think that if someone starts at a lower temperature, it suggests a bad prognosticator.Dr. Patrick Lyden: You know accidental hypothermia and therapeutic hypothermia are different animals except they have one word in common. The mechanism of injury in that body is totally different. Why the patient is hypothermic is completely different. In accidental hypothermia, you have either shock or polytrauma or other issues so that other organs suffer other injuries. When you have a simple cerebral injury, a stroke, or uncomplicated cardiac arrest with return of spontaneous circulation (ROSC) and the patient is metabolically stable, that is a completely different issue. For the trauma surgeon rewarming, I would not even pretend to know what you need to do for accidental hypothermia but for us despite a lot of fear of other organ damage, we monitored a lot in the ICTUS trial, including liver function every 6 hours and kidney function and everything you can imagine, we saw none of the things that one would see in the accidental hypothermia world, so when we do it to an intact organism, we can go down quickly and come up quickly and not worry about the rest of the body.Question:Would the in-hospital cardiac arrest patients be a group of patients in whom you could do a study wherein you could introduce hypothermia very early?Dr. Justin Lundbye: You are right because you have all the resources on site. The caveat with the in-hospital cardiac arrest patients is that most of them are nonshockable. Although some signals indicate that if we do cool these patients they do better but their overall prognosis is poor. But to your point, you do have everything onsite. It would certainly be easier to initiate that type of study.Dr. Michael Kurz: From our own experience, yes resources are readily available for in-hospital cardiac arrest. However, the decision to be able to go ahead with hypothermia is significantly more complicated. If a patient arrests outside the hospital, by definition they were healthier when the arrest occurred than their in-hospital counterpart. In the in-hospital setting, there are any number of consultants with whom you must discuss the relevant issues: for example, the patient had abdominal surgery 7 days ago, can I still cool them? Or the patient has a recent craniotomy, can I still cool them? The time to discuss and render a decision is longer.Question:If we are talking about in-hospital cardiac arrests, they are comatose so what if they have had a surgery7 days ago, they are essentially brain dead so why not just go ahead and start therapeutic hypothermia?Dr. Michael Kurz: There are a number of potential contraindications that may present based upon the underlying condition requiring the admission that forced the patient to be hospitalized in the first place. Those have to be taken into account before you go ahead and cool them. My cardiothoracic surgeon would not be really excited if I took his or her patient with recent three vessel coronary artery bypass graft and cooled him or her without discussing it. They have unique knowledge from the surgical case that I do not and cannot consider, but is essential for a successful outcome.Dr. Justin Lundbye: There are a lot of nuances. At one point you have to tackle them, but the first time you cool an in-hospital cardiac arrest patient because they are not that commonly done, you do have to talk to the surgeon and any other players involved. I think once you have done a couple of these cases, you just have to tackle these nuances initially.Dr. Michael Kurz: We fundamentally agree, but there are a lot of these nuances that have to be addressed, especially when there are five or six consultants.Dr. Patrick Lyden: One of the big nuances is that you do not have the time of onset of the cardiac arrest half the time. So if you are walking down the sidewalk, there are tons of witnesses, but if you are in the hospital room by yourself and you are not on telemetry, people are checking on them every 6 hours and there may not be a time of onset.Dr. Justin Lundbye: Even if the patient is on telemetry, the time at which point you have loss of pulse to asystole is about 20 minutes and the time from respiratory arrest to asystole is about 30 minutes. During that interval, all you see is bradycardia and if you have telemetry staff who are busy and they just see bradycardia, they may not react to that. Unfortunately during that whole time, the patient's metabolic milieu is worsening and the rescue team is dealing with a 30-minute downtime.Comment: Justin, I think that you showed the 1990 article that we did that if we cooled the rat during the transient global cerebral ischemia insult and let the animal live for 2 months, that CA1 hippocampus looked normal, whereas if we waited hours after, there was progressive decrease of surviving neurons. If you can have cooling on board in any situation we are talking about, I guess not cardiac arrest, but myocardial infarction we talked about and things of this nature, therapeutic hypothermia really knocks down the reperfusion injury and really targets those postinjury events.Key References from Panel ParticipantsBergman L, Lundbye JB. Acid-base optimization during hypothermia. Best Pract Res Clin Anaesthesiol 2015;29:465–470. 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A cool approach to reducing electrode-induced trauma: localized therapeutic hypothermia conserves residual hearing in cochlear implantation. Hear Res 2016;339:32–39. Crossref, Medline, Google ScholarFiguresReferencesRelatedDetailsCited byPerspectives on Temperature Management Graham Nichol, Kees H. Polderman, Hans Friberg, Michael Kurz, and Gregory Kapinos5 December 2018 | Therapeutic Hypothermia and Temperature Management, Vol. 8, No. 4Unique Uses of Cooling Strategies Patrick Lyden, Jonathan Paul, Shoji Yokobori, and Joseph Cuschieri1 September 2018 | Therapeutic Hypothermia and Temperature Management, Vol. 8, No. 3Temperature Management in Neurological and Neurosurgical Intensive Care Unit Justin Lundbye, David M. Greer, Kees H. Polderman, and Shoji Yokobori1 June 2018 | Therapeutic Hypothermia and Temperature Management, Vol. 8, No. 2 Volume 8Issue 1Mar 2018 InformationCopyright 2018, Mary Ann Liebert, Inc.To cite this article:Michael Kurz, Patrick Lyden, Justin Lundbye, and Suhrud Rajguru.Local to Systemic Use of Hypothermia.Therapeutic Hypothermia and Temperature Management.Mar 2018.4-8.http://doi.org/10.1089/ther.2018.29041.mjkPublished in Volume: 8 Issue 1: March 1, 2018Online Ahead of Print:January 23, 2018PDF download