THERAPEUTIC HYPOTHERMIA AND TEMPERATURE MANAGEMENT Volume 3, Number 1, 2013 ª Mary Ann Liebert, Inc. DOI: 10.1089/ther.2013.1500

Expert Panel Discussions

Preclinical and Clinical Studies Targeting Therapeutic Hypothermia in Cerebral Ischemia and Stroke Moderator: Patrick Lyden, MD1 Participants: Fred Colbourne, PhD,2 Patrick Lyden, MD,1 and Stefan Schwab, MD 3

individuals as they treat these very complex injuries with various cooling strategies.

Among the first neurological disorders to be investigated with mild hypothermia were transient forebrain ischemia and focal stroke. In these early studies, several laboratories reported the beneficial effects of mild hypothermia and, as a consequence, the importance of measuring brain temperature directly to enhance the reproducibility of models as well as to protect against ischemic cell death. From these early preclinical studies, hypothermia has now entered clinical investigations aimed at uncovering the potential for therapeutic hypothermia and temperature management programs to make a difference in patients’ lives. Although the most obvious successful translation has been in the area of out-ofhospital cardiac arrest, new studies are showing that therapeutic hypothermia may also be useful during acute stroke as well as extending the therapeutic window for neuroprotective and thrombolytic treatments. A series of state-of-the-art lectures presented at the 2012 Therapeutic Hypothermia and Temperature Management Meeting in Miami brought together experts in the field of therapeutic hypothermia targeting cerebral ischemia and stroke. Dr. Fred Colbourne, Center for Neuroscience and the Department of Psychology at the University of Alberta, Canada, addressed mechanisms of hypothermic protection in stroke and hemorrhagic infarction. Dr. Colbourne and colleagues have been involved for many years assessing therapeutic hypothermia in models of brain injury including hemorrhagic infarction. In addition to providing examples of efficacy of hypothermia in different global and focal ischemia models, Dr. Colbourne also talked about safety concerns in terms of systemic complications and side effects of this promising therapy. Dr. Patrick Lyden, Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, updated the attendees regarding the ICTuS2-3 trial on therapeutic hypothermia for acute stroke. He discussed rates of pneumonia seen in subjects with prolonged cooling, as well as potential combination approaches targeting shivering and other consequences of the cooling protocol. Dr. Stefan Schwab, Professor and Chair, Department of Neurology, University ErlangenNurnberg, Germany, discussed the ICTuS L Trial and infections associated with the hypothermic treatment. An update regarding the EuroHYP Trial was also provided to the attendees. It was clear from the presentations that the use of hypothermia is providing new challenges for treating physicians, nurses, and critical care

Question: Sedating with meperedine and buspirone, buspirone in particular has to be given orally. Do you put an NG [nasal gastric] in everybody, or do you do a real swallow evaluation before each dosing? It appears to be a very complicated issue technically. Dr. Patrick Lyden: In theory, it’s very simple. The first buspirone dose has to be gotten in very quickly, typically the tPA is still running, and in our hospital, the nurses have gotten hold of the idea that they can’t put an NG tube in for 24 hours after tPA treatment, so it creates a real problem. The microaspiration issue is legitimate; it’s been proven it really happens, so we do try to get an NG tube in as soon as we can. In some cases, we are able to get it in before the tPA, but most of the time we can’t. The buspar can be crushed and actually put into the mouth with a little bit of applesauce, and most patients don’t aspirate that. But as you say, that is before the demerol. After the demerol, it really has to be by NG tube. Question: What was the explanation for the higher rates of pneumonia in the ICTuS L trial? Dr. Patrick Lyden: So in ICTuS L, there were two problems. One is I don’t think we appreciated the frequency of aspiration in our patients. All of the pneumonias have the characteristic of an aspiration pneumonia in terms of location and flora that was cultured. But we also had another problem, which is that in ICTuS L, the cooled patients were admitted to the ICU and one study team member was at the bedside for 36 hours. Constant attendance of these patients throughout the night was conducted. The normothermic patients were treated with tPA and admitted to a ward. So in contrast, there was not the similar vigilance with the normothermics. So there was a significant bias toward finding the AEs in the cooled patients and then there was no definition of pneumonia. Anything white on chest x-ray was called pneumonia in

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Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, California. Center for Neuroscience, Department of Psychology, University of Alberta, Alberta, Canada. Department of Neurology, University of Erlangen-Nurnberg, Erlangen, Germany.

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4 ICTuS L. Now we use the CDC criteria for diagnosing pneumonia. It cannot be called pneumonia unless it satisfies all CDC criteria, and with that definition in place, with aspiration precautions in place, with NG tubes and gastric drainage, our incidence of pneumonia is equal in both groups and significantly reduced from the previous study. Question: Do you have data about the microorganisms that cause the pneumonia? Dr. Patrick Lyden: We do. Being a neurologist and needing a lot of help from real doctors, I’m told that the cultures were consistent with aspiration. Question: I have a question regarding just precautions for reducing the risk of aspiration pneumonia in ventilated patients. We often ensure that their head in fact is 30 or higher to reduce the frequency of aspirations. So are those types of things followed in those patients with a minimum head of bed at 30? Dr. Patrick Lyden: The full protocol is exactly that. NG drainage to make sure there is nothing in the stomach, head of the bed elevated, daily surveillance, actually listening to the lungs and looking at the patient, looking at white blood count. Also, a very low threshold for chest x-ray and low threshold for prophylactic antibiotics. The head of the bed elevated is a problem now because there are data that perfusion is improved with the head of the bed flat. So we have discussions with my fellows pulling on the bed one way and me pulling on the bed the other way. I don’t know what the right answer is, but I’m going with aspiration precautions over a theoretical perfusion benefit with head of the bed. Question: Dr. Colbourne, very interesting presentation. I was very intrigued with the continuous hypothermia induced in animals. Did that have any behavioral manifestation itself produced by prolonged cooling? I assume by that approach you must be reducing brain metabolism by almost 30%. Dr. Fred Colbourne: For example, with prolonged systemic cooling, the animals will shiver initially and become clearly hypoactive. For the focal cooling, we didn’t really see shivering. They seem to be perhaps a little bit less active, but we didn’t see any abnormalities that were obvious. I thought maybe that since we were cooling motor cortex that the rats might turn in their cage for example. We didn’t see that. It is a mild cooling down to around 33C that we are using. So perhaps if we were to cool more when you actually do shut down neuronal activity, then we would see that consequence. Question: In that context, have you ever contemplated using supercooling strategies to see how low you can go to enhance protection? I know it’s technically challenging, but perhaps putting artificial carriers that further chill the cortex, you may be able to drop the temperature deeper, hold it longer, and maybe improve protection. Dr. Fred Colbourne: I think right now we can get it to around 30C, and with specialized cooling devices, you can get it colder locally. The problem is doing that for long periods in awake animals, the Peltier thermoelectric cooling

EXPERT PANEL DISCUSSION devices are too large and take too much current to allow it to be done in freely moving animals. So with our implanted cooling coil method, right now we can cool to 30C. Going lower than that might be more neuroprotective, but I think in patients we are not going to get selective head cooling down to that range without also getting systemic cooling. So it may not be entirely relevant to cool to such a level for long periods. Question: I want to ask a follow-up question, if you don’t mind, Fred. As Stefan Schwab suggested, what we do in humans is actually quite different. So we are combining hypothermia with Buspar, meperidine, and possibly magnesium, all of which have been reported in isolated small studies to show protective effects. Have you ever done a study where you loaded the animals with all of those drugs, or those drugs and not hypothermia, just to see the neuroprotective effect? Dr. Fred Colbourne: We’ve done a little bit of work combining drugs like valium with hypothermia to see if that added any extra benefit, and it did not. We haven’t studied meperidine, although we have plans to do that, especially in the local cooling model. We can then take shivering out of the equation and see if it is actually neuroprotective with or without cooling. So perhaps by the next meeting, I may present new data on that. But it is essential that that be done. Question: I’m curious as to the panel’s thought about the combination of cooling with hemicraniectomy for the larger MCA strokes. There’s some small case series out there. It’s a strategy that we’ve applied in the younger, more robust patients. Dr. Stefan Schwab: Well, we have conducted those studies for the last years, and only, as you said, in certain cases. Usually, I think the craniectomy in ischemic stroke is already the ICP relief that you are aiming for. But there are some patients which have, especially those with basal shift on the brain stem that cannot be treated with craniectomy alone. There, we also institute hypothermia. There is an idea that this is beneficial for both in terms of ICP control, but there is no formal trial. It’s just a small series of 10–15 patients. Dr. Patrick Lyden: I want to add that that is a different use of hypothermia. Controlling edema and ICP management with hypothermic treatment is a different trial. ICTuS and EuroHYP are targeted at the neuroprotective role. So it needs to be started early and continued for a short period of time. Whether we should continue cooling the patient as a way of controlling ICP or edema in my mind is a separate study. That would be a different protocol. In that case, I would really like to see an endpoint controlled duration and depth if there were a biomarker that could be used to follow the patient and titrate the longer-term hypothermia over several days. But that is different from a neuroprotective philosophy. Comment: The brain temperatures have to be lower on the craniectomy side. How long it stays lower is not necessarily clear, but once the deep depression is gone, the hemisphere is back and you can put brain-tissue temperature probes on both sides to see that that hemisphere is actually at a lower temperature. Clearly, there is this edema benefit; there is also

EXPERT PANEL DISCUSSION angiographically of the enhancement of cerebral circulation collaterally. Comment: Yes, we think of it initially just in terms of treating ICP, but in fact there is this change in terms of the blood flow dynamics to that hemisphere that comes from collateral circulation. We observe improved venous outflow and a change in the microcirculation beyond that of what would be expected just from ICP control. So we don’t truly understand all the effects. There are certainly many consequences in the delayed phenomenon with syndrome trephine that we run into which are also almost the reverse and are quite difficult to manage. But acutely, it’s more than pressure; clearly, these alternatives are initiated because of control of pressure and control of shift. But we are seeing that there are more changes than just a pressure phenomenon. Dr. Patrick Lyden: I have a hard time selling the idea of an invasive femoral line to cool patients, let alone hemicraniectomy. Dr. Fred Colbourne: If I could add just a comment to that, we are not doing hemicraniectomy, but we are starting to measure ICP in rodents after stroke, which is technically difficult. We have a method now that allows us to measure ICP for days. We are going to be starting to look at how cooling influences that reading because changes in edema are not necessarily the same as the pressure response. Question: I have a question for both the European and American studies, since you are technically measuring the effect on reperfusion injury with hypothermia. Does either study intend to look at recanalization toward the end with either CTA or transcranial doppler? Dr. Patrick Lyden: So in ICTuS, we have submitted a supplemental grant application with our centers that have the capability to do posttreatment imaging to look at both recanalization and reperfusion. Hopefully, there are members of the study section listening to this important need. [Editor’s Note: the supplemental study, HASTIER, was approved by the US National Institutes of Health in 2012 and is accepting application from interested sites.] Dr. Stefan Schwab: We have the same. We have ultrasound work and hypothermia really monitoring when patients reperfuse under therapy and also CT angiography, which is suggested at 24 hours. Question: A question for Stefan on the European study. You are looking at combining two different approaches: surface versus intravascular cooling. Do you have any feasibility preclinical data to show that you are actually going to be able to get patients to target temperature with the surface methods? About a decade ago, our institution did a feasibility study where we started and had to abort after three patients because the dose of sedative required with the meperidine got to almost intubation levels as we were approaching 35C and getting lower. So we were never able to take safely, particular at the NIHs, I mean, both of these patients, our first two had NIHs of more than 15, and in those patients, as I said, we got to almost intubation levels in meperidine, and we are still not

5 able to get below that threshold. So as you are combining these two, there is a real potential for difficulties in lumping the data together. Dr. Stefan Schwab: That is a great question and that is actually also something that is asked for, so there are some data. I am aware of what you did more than 10 years ago, and this will be an issue. Response: So may I have a comment on this? There is a study that finished a few months ago in Helsinki. They did around 50 patients with surface cooling. I think the individualized target temperature was between 34C and 35C, so actually this was working. But also the incidence of pneumonia was increased. Dr. Patrick Lyden: I think it is important to state that all surface cooling is not created equal. There are more advanced methods that are more powerful, and get the patient colder quicker. Whether they are more tolerated than convective cooling, for example, remains to be seen. But it is important especially with surface technology not to mix apples and oranges. There are different ways of cooling patients with surface methods. Question: So let’s talk about the exciting findings that moderate hypothermia has the ability to affect neurogenesis. Isn’t it potentially exciting that you have a therapy that could potentially target cell death and then actually enhance reparative mechanisms after brain or spinal cord injury? So I think Dr. Colbourne’s laboratory and colleagues have really pioneered an area that we are going to be hearing about in the future. Dr. Fred Colbourne: I guess my bias is that most of the recovery after stroke, whether it is global ischemia models or the focal ischemia models, is not due to neurogenesis; it is due to things like synaptogenesis. I think that is the more important mechanism. Neurogenesis certainly is a player, and we are very relieved not to see a harmful effect on neurogenesis with cooling, but I think we need to keep in mind that responses will depend upon several factors including the age of the animal. Studies looking in young animals, for example, will find different results than in older animals where there is not as much neurogenesis in the dentate gyrus. It is really hard causally to link these cellular changes to behavioral benefits seen with hypothermia. Similarly, a problem in the plasticity field is linking those changes with actual behavioral data. Is it the neurogenesis that is beneficial or is it some other mechanism? That’s a big challenge. Comment: Specifically, in the traumatic brain injury literature, they are finding that neurogenesis in the dentate gyrus is extremely important in the recovery of learning and memory. If you specifically knock out neurogenesis, the rats just don’t function as well as they should after injury. So I think the literature is supporting the concept that neurogenesis within the dentate gyrus specifically is associated with functional improvement. In the spinal cord, we just discovered a whole new series of stem cells and progenitor cells that also appear to be temperature sensitive. So I think

6 this is going to be a new research area that is going to open up. Comment: I do agree that, in traumatic brain injury, many groups have shown the importance of neurogenesis. But I do agree with Fred, that I think a very important aspect for us is to look at the plastic changes both after trauma and stroke. My concern is that many of those responses we see may not be adaptive for the animal or the patient. They may be maladaptive. So we may have a double whammy of trying to rewire the brain. I think there is more urgency in my estimation at the moment on saving or reversing the initial lesion rather than focusing on neurogenesis or plasticity. It’s really a tough can of worms. But I think there is more and more evidence that plastic changes are probably the ‘‘seat of the soul’’ in the response of these animals and patients. Dr. Fred Colbourne: So I guess it’s important to try to find measures to decide when to end the cooling, and that should include some evaluation of plasticity, maybe electrophysiological changes or something else that will help us to decide. Cooling for long periods, I think, is going to have some harmful effects on plasticity when we look carefully enough. Question: We are finding out that newly generated cells, progenitor cells in the dentate and spinal cord, are very vulnerable early on to the same things that we think adult neurons are vulnerable to, including apoptotic mechanisms and excitotoxicity. So if lowered temperature can protect those cells when they are being born, they may ultimately be integrated into functional circuits that might be a very positive thing. You’ll be seeing these types of neurogenic studies more and more in the literature. What is the importance of that reparative strategy in terms of saving tissue with pharmacotherapy or hypothermia? Dr. Fred Colbourne: We have to be careful of the other drugs that we are giving along with cooling to evaluate whether they are also having effects on plasticity markers.

EXPERT PANEL DISCUSSION Key References from Panel Participants Clark DL, Penner M, Wowk S, Orellana-Jordan I, Colbourne F. Treatments (12 and 48 h) with systemic and brain-selective hypothermia techniques after permanent focal cerebral ischemia in rat. Exp Neurol 2009;220:391–399. Guluma KZ, Liu L, Hemmen TM, Acharya AB, Rapp KS, Raman R, Lyden PD. Therapeutic hypothermia is associated with a decrease in urine output in acute stroke patients. Resuscitation 2010;81:1642–1647. Hemmen TM, Lyden PD. Hypothermia after acute ischemic stroke. J Neurotrauma 2009;26:387–391. Hemmen TM, Raman R, Guluma KZ, Meyer BC, Gomes JA, Cruz-Flores S, Wijman CA, Rapp KS, Grotta JC, Lyden PD; ICTuS-L Investigators. Intravenous thrombolysis plus hypothermia for acute treatment of ischemic stroke (ICTuS-L): final results. Stroke 2010;41:2265–2270. Kallmu¨nzer B, Kollmar R, Schwab S. Therapeutic hypothermia in acute brain injury. Nervenarzt 2012;83:975–981. Kallmu¨nzer B, Schwab S, Kollmar R. Mild hypothermia of 34C reduces side effects of rt-PA treatment after thromboembolic stroke in rats. Exp Transl Stroke Med 2012;4:3. Koehn J, Kollmar R, Cimpianu CL, Kallmu¨nzer B, Moeller S, Schwab S, Hilz MJ. Head and neck cooling decreases tympanic and skin temperature, but significantly increases blood pressure. Stroke 2012;43:2142–2148. MacLellan CL, Clark DL, Silasi G, Colbourne F. Use of prolonged hypothermia to treat ischemic and hemorrhagic stroke. J Neurotrauma 2009;26:313–323. Silasi G, Colbourne F. Therapeutic hypothermia influences cell genesis and survival in the rat hippocampus following global ischemia. J Cereb Blood Flow Metab 2011;31:1725–1735. Silasi G, Klahr AC, Hackett MJ, Auriat AM, Nichol H, Colbourne F. Prolonged therapeutic hypothermia does not adversely impact neuroplasticity after global ischemia in rats. J Cereb Blood Flow Metab 2012;32:1525–1534. Staykov D, Wagner I, Volbers B, Doerfler A, Schwab S, Kollmar R. Mild prolonged hypothermia for large intracerebral hemorrhage. Neurocrit Care 2012; Epub ahead of print. Yenari MA, Colbourne F, Hemmen TM, Han HS, Krieger D. Therapeutic hypothermia in stroke. Stroke Res Treat 2011; 2011:157969.

Preclinical and clinical studies targeting therapeutic hypothermia in cerebral ischemia and stroke.

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