During the Sixth Annual Therapeutic Hypothermia and Temperature Management Meeting in Miami, an expert panel discussion on the continued use of therapeutic hypothermia for stroke and cerebral ischemia was organized. The moderator was Dr. Justin Lundbye, Hospital of Central Connecticut, New Britain, Connecticut, Dr. Patrick Lyden, Department of Neurology, Cedars-Medical Center, Los Angeles California, discussed the ICTuS two final results on the use of thrombolysis and hypothermia to improve outcomes in acute stroke patients. Primary and secondary outcome measures were summarized, as well as safety issues. Dr. Kees Polderman, Department of Critical Care, University of Pittsburgh Medical Center, discussed the use of hypothermia in cardiogenic and septic shock. For this lecture, topics also included the effects of temperature on heart and vascular tone, as well as renal function. Dr. Stefan Schwab, Department of Neurology, Friedrich-Alexander University, Erlangen, spoke on the use of hypothermia in acute intracerebral hemorrhage. Topics included the pathogenesis of clinical
ICH, as well as encouraging preclinical findings. The methods and outcome measures used in the
TTM-ICH pilot clinical study were summarized and outcome measures and results discussed. This expert panel discussion was very informative and touched upon some new questions and ideas regarding the use of therapeutic hypothermia targeting this patient population.
Question: Dr. Lyden this is a question about the revised ICTUS protocol and the new devices that have shown such a phenomenal benefit. My understanding is that most of those or many of them will intubate the patient before the treatment, is that the case? And if so, how do you account for that with the design of the trial?
Dr. Patrick Lyden: I am not an interventionist, but I talk to them every day and what they tell me is that these are moving targets, so there are some centers that insist on general anesthesia and paralysis and other centers that insist on sedation. There is a lot of dogma being thrown around about which one is better than the other. Our protocol is written to allow local practice. I don't think that there science is mature enough yet that we can adopt a protocol and specify that is what is going to happen. We have little ways to go before ICTUS 3: we have to do a little feasibility work so that we can show that we combine endovascular hypothermia with intra-arterial thrombectomy: that pilot study is probably going to take about a year, so maybe in the next year some consensus will emerge from the interventionist community about do you anesthetize and how do you do it.
Dr. Stefan Schwab: Do you think the meperidine was a suspect for almost doubling the mortality rate or what is your explanation for that?
Dr. Patrick Lyden: I am unsure, but I suspect meperidine because we saw, if you recall the summary of stroke studies that somebody showed this morning, pneumonia is a recurrent theme in hypothermia, and I thought it was due to sedation. I actually thought it was due to selection bias, and overcalling it, but with ICTUS 2 we used very rigorous surveillance for pneumonia in both groups and precise definition using Centers for Disease Control criteria and still saw doubling. So I think it is the pneumonia, I think it is the aspiration pneumonia, I think it is due to the meperidine but maybe there are other problems that we don't know about.
Dr. Kees H. Polderman: We did something similar to what you are planning in terms of pilot testing hypothermia in patients undergoing thrombectomy. We did 21 patients with a target temperature of 32.5°. The main shivering prevention methods were skin counter warming and magnesium. We discussed this a couple of times before so we need very little meperidine. I think the highest dose over 24 hours in one patient was 300 mg; the average is 125 mg. So, if you go to this lower temperature and you do the skin counter warming and use the magnesium, you reduce your needs. We don't see this rate of pneumonia from just 21 patients, certainly the outcomes are better than historical controls. We cooled for 24 hours. What we see is that the requirement for shivering management is low in the maintenance phase and when we start rewarming we actually need a little more because the gradient between core and skin goes down. I think that if you are ever to tweak this protocol and use a couple of other drugs that are nonsedating, then that will probably help solve the problem.
Question: These are extremely interesting series of talks. My question is directed to Stefan with possible answers from the others. We look at an ICH trial as you are demonstrating that has eight continuous days of temperature management. I know Mary Kay and others will share with us the burden that adds to tremendous critical care nursing. Pat, in his talk, discussed a short and deep pulse of hypothermia that seems to be effective in acute ischemic stroke. Are there any data or thoughts about that type of a therapy, a short direct deep hypothermia for intracranial hemorrhage?
Dr. Stefan Schwab: No, I don't think so. I tried to show that the treatment target is another one. We aimed to treat edema formation and as you know edema development follows different rules than ischemic stroke and it wouldn't make sense in my eyes to do short shots of hypothermia. I see this long-term hypothermia as possible indication for subarachnoid hemorrhage where we treat vasospasms, which may require a longer duration of hypothermia very similar to ICH. We have no evidence how to treat vasospasm in SAH besides nimodipine, so I think there are more data coming out that this could be an option for those patients.
Dr. Patrick Lyden: Let me emphasize that I am thinking about the neurons and neuroprotection and when you are talking about edema, we are thinking about the blood−brain barrier, endothelial cells, and astrocytes, to some extent very different things that we have mixed together traditionally. One lesson that I have taken from my experience is that these are separate processes and what I would actually like to do is to cool a patient whether they have a hemorrhage or ischemic stroke quickly and deeply for a short amount of time and then warm them up, let the body's repair system engage, and observe them for edema. If they develop edema, whether it is due to perihematoma edema or ischemic edema, then cool them again and return them to a protective level to prevent or treat that edema.
Dr. Kees H. Polderman: I would add to that, I am not so sure that the work load has so much increased if you stipulate that you would have to do fever management anyway. One hundred percent of those patients get fever so you are doing active temperature control in many ways, maintaining hypothermia is actually easier less work for the nurses. Mary Kay can comment on that later, but the shivering is less and there is a better response to skin counter warming. I am not sure the work load will be that much increased if the alternative is fever management.
Question: Stefan, regarding the CLEAR IVH trial, one of the reasons we think it was not positive was because they incorporated small lesions. So my question is could you tell us what was the rationale behind picking 25 to 50 cc because you see edema in these cases but it is not the edema that would get the patient into trouble. I've yet to see a 15 cc ICH get a patient into trouble with edema. I have never seen that in about 20 years that I have been doing this so I would like to understand what is the rationale for that volume?
Dr. Stefan Schwab: I do not know for the 15 cc, but I must say that 25 cc which is the lower edge and I think it comes from Dan; I think he brought in the idea that of the 20 cc being the cut of the positive outcome in the initial analysis before he started with CLEAR. So I would agree with you that we would hardly see any effects in these smaller hemorrhages.
Dr. Justin Lundbye: Kees, there is a syndrome, long QT syndrome, that can occur obviously that is a genetic condition, which puts patients at risk, and when you induce therapeutic hypothermia and create hyperbradycardia which may actually predispose torsades. I would like to hear from the audience on how you mitigate torsades in that patient population if it does occur?
Dr. Kees H. Polderman: It is an excellent point. It is one of the many reasons why I like magnesium drips for the shivering control because it also is effective against torsades. In general, you have to watch very carefully the medications that you are given, try to avoid things that can add to that, azithromycin and midazolam can indirectly add to that. So that is something that we should be aware of. That said, I have not seen this problem occur in this way. I have never had a patient develop torsade during hypothermia. But I use magnesium and keep it at a high normal level and now use it for shivering control. I think that maybe by itself and if you avoid drugs that add to it, it will prevent that problem from occurring. But it is an excellent point.
Question: In the recent severe
TBI Eurotherm trial they actually targeted hypothermia to
ICP elevations so instead of doing it 8 days of cooling for intracerebral hemorrhage, which seemed to be working so I am not saying that you should do this, is there another strategy to look at the ICP and target the ICP elevations in that patient population, has that been tried?
Dr. Stefan Schwab: I think what we know on the ICP management in ischemic stroke is that you are always behind when the ICP is already elevated. It could be a strategy, but I am not aware of any studies on that at the moment.
Dr. Kees H. Polderman: If you look on one of my first trials that was on TBI, using hypothermia for ICP control and even in that trial, which had 136 patients, we saw benefits only in the patients with early cooling. With late ICP rise we didn't see harm, but we saw no benefit. The benefit is only if you do early cooling. There is actually no study that I am aware of with late ICP control in any indication that shows outcome benefits. For sure you can control ICP the only exception is encephalopathy, that is, generalized edema. So, I would be careful with that; in traumatic brain injury there is evidence that this might actually be harmful. And is certainly not beneficial.
Question: Kees, I think you showed data from a substudy of TTM where it suggested that 33° group had lower cardiac output. Did I understand that correctly?
Dr. Kees H. Polderman: After rewarming yes.
Question: So I believe that was the same study which reported that the patients in the 33° group received a higher dose of propofol than the 36° group so I think this may have contributed.
Question: Pat can I ask you to clarify, if I understood your results, it seems to me the issue, in part, that the patients didn't get cold enough, fast enough? But I don't know whether I have a sense of whether that was an issue of the method that you were using, was it too slow or whether people did not comply with what you intended them to do. Could you comment on whether or not you think it is an issue of technology or nonadherence?
Dr. Patrick Lyden: It is a little bit complicated by the fact that we couldn't take a temperature for 30 minutes; once you begin cooling we were using the Innercool catheter that has a thermistor and you do not want to interrupt cooling to see if you are at target, you let it run for 20–30 minutes before you take a temperature. Then you do not take another temperature for about an hour. There is a little bit of a black box that we are trying to understand what went wrong in there. But the recorded time to target was about an hour, which is really good for stroke studies, but not for what we need to prove benefit to the degree that we see in animals. In addition to that, and I know from personally doing many patients myself, if you did everything correctly patients will get to target within 20 minutes. If they had their buspirone on board 45 minutes before and you loaded them with meperidine and then loaded them with ice cold saline and then got the catheter in and got it to work right, you could easily cool patients from normothermia to hypothermia, but I know that very few of our sites did that every single time in every single case. I think the worst mistake that we made in many cases was to give the ice saline first and then move the patient to the ICU and then start the meperidine and then start the buspirone and somewhere in there put in a catheter and that's just not going to get an effective hypothermia. We do not have excellent data to tabulate that. I just know from looking at cases that we have had a lot of problems with protocol adherence. The patient got the catheter inserted after moving to the ICU in too many of our cases.
Dr. Justin Lundbye: What medication were you using to reduce pneumonia risk?
Dr. Patrick Lyden: The pneumonia protocol involved head of the bed elevated, gastric drainage, daily surveillance, and very low threshold for starting empiric antibiotics.
Dr. Justin Lundbye:
So there was no sort of proactive initiation of antibiotics?
Dr. Patrick Lyden: No prophylactic antibiotics and no prophylactic mouth hygiene.
Dr. Stefan Schwab: Did you see a center effect for those who did more hypothermia?
Dr. Patrick Lyden: We tested for a center effect and then we tested for a volume effect and none of those tested positive. Very few patients, only 51 patients per protocol, but we could not detect a center effect or a volume effect. When I threw out the first two cases that everybody did just to get rid of the learning cases, the point estimate went in the wrong direction.
Dr. Justin Lundbye: One of the things that we did when we started our hypothermia studies many years ago, we used prophylactic antibiotics in all our patients and there are arguments in both directions for that. Obviously we do not have a control arm, and one of the things we have seen is that our infection rate in general is very low for those patients during that time.
Question: Pat, I was interested in your new data showing that a restricted period of deep hypothermia is potentially protective in a model of transient
MCA occlusion. I know you remember the data with transient global ischemia where we found only transient protection of the CA1 hippocampus and no chronic improvements in learning and memory. So again, I just wonder if that is what you may end up seeing with only a brief period of deep hypothermia with MCAo?
Dr. Patrick Lyden: The animal literature is quite difficult to tease all of this out, because you have different end points and there are different strategies. Colbourne showed really elegantly that the longer you wait to start hypothermia the longer you need to cool, so that got all of us thinking that 24 hours are needed for cooling, especially in humans who come in on an average 6 hours after their stroke onset. I am not saying that we should necessarily go to 33 and back to 37. We need to go to 33 as fast and as hard as we can. But what we do after that I am not sure at all, is a very long ramp. Is it to go to 35 for a while, I think that is going to answer your question.
