THERAPEUTIC HYPOTHERMIA AND TEMPERATURE MANAGEMENT Volume 1, Number 3, 2011 ª Mary Ann Liebert, Inc. DOI: 10.1089/ther.2011.1508

Developing Clinical Trial in Acute Myocardial Infarction* Simon Dixon, M.D.,1 Hans Friberg, M.D.,2 Magnus Ohman, M.D.,3 and David Erlinge, M.D.4

New strategies, including therapeutic hypothermia to target myocardial infarction (MI) following cardiac arrest and cardiogenic shock, are an active research area. Cooling in myocardial infarction has a rich history in terms of targeting various pathophysiological mechanisms and reducing infarct size. Dr. Simon Dixon at Beaumont Hospital summarized animal studies indicating that hypothermia may blunt the detrimental effects of reperfusion injury. Factors associated with cooling include timing and depth of hypothermia, duration of cooling, and ischemic severity. Studies using swine models of myocardial infarction have clarified the therapeutic window for cooling as well as strategies to reduce temperature. Also, late onset of cooling, targeting patterns of reperfusion injury, has also been evaluated with different degrees of success. Clinical trials have been initiated, including the COOL-MI II trial, which was discontinued due to insufficient funding. Thus, although there is a significant amount of preclinical data indicating that cooling is protective in experimental models of ischemia reperfusion, the effect appears to be time and depth dependent with cooling after reperfusion having minimal impact on infarct size. Dr. Magnus Ohman, Duke Medical Center, discussed cardiogenic shock and current experiences with hypothermia in that patient population. Dr. David Erlinge, Lund University, indicated that more clinical studies should be done if optimal cooling can be achieved prior to reperfusion. Based on current data, this cooling approach may have the best effect in terms of improving outcome. In this regard, rapid intravascular cooling in myocardial infarction as an adjunctive to percutaneous coronary intervention (RAPID MI-ICE) has been initiated in patients to determine safety and efficacy. Recent studies indicate that the rapid induction of hypothermia with cold saline and endovascular catheters is safe and feasible in awake patients with acute MI. In these patients, target temperature (less than 35C) is reached before perfusion with myocardial infarction being significantly reduced. The CHILL-MI trial will be a randomized controlled study using central venous catheter core cooling combined with cold saline as an adjunct to coronary intervention for the treatment of acute MI. The primary endpoint for this study will be MRI infarct size at approximately four days after the injury. The use of cold saline combined with catheter cooling may be the best approach, while short post reperfusion cooling durations may be optimal to avoid the need for intensive care unit (ICU) care and the avoidance of complication

in immobilized patients. These studies indicate that various cooling strategies may be appropriate for subjects undergoing acute coronary syndromes including myocardial infarction and cardiac arrest. Dr. Hans Friberg, Lund University, summarized the evidence evaluation process for assessing cardiac arrest patients and hypothermic therapy. Adverse effects in out-of-hospital patients treated with hypothermia were also reviewed. Question: Thank you to all of our speakers for the excellent presentations. I would like to start my questions with Professor Friberg, if I may. You correctly said that somatosensory evoked potentials (SSEP) monitoring is very good but has low sensitivity. Just two or three questions. With your markers of prognostications, what is your opinion regarding the influence of kidney failure? Or do we have bad luck, and we can’t use anything in a patient with kidney failure? Second question. Clinical examination of a patient with increased intracranial pressure with brain edema on the CT or on the MRI, do you wake them up, which would mean stopping the sedation, analgesia, etc.? And third question, you talked about paralytics and said that we can give paralytics to these patients. Do I understand you correctly that you give paralytics without sedation and analgesia? If you give sedation and analgesia and, in particular, sedative drugs like propofol or midazolam, these are very powerful anti-epileptic drugs, per se. Therefore I have difficulties understanding your high rate of status epilepticus. I’m a neurologist, therefore, I am highly interested, and I do a lot of similar stuff as you do. Dr. Friberg: Regarding the first question about neuron specific enolase (NSE), renal failure is not a big issue in these patients, we have indeed very few. So I really couldn’t tell you. I don’t know the literature that well regarding renal failure and how that affects NSE. In this patient cohort of 100 patients, none of them actually developed renal failure of any significance. Maybe someone else could answer that question regarding NSE and renal failure? Question: Okay, so I will look it up and tell you later. Second question. Patients who develop brain edema and who are declared brain dead, is that what you are saying? You said

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William Beaumont Hospital, Royal Oak, Michigan. Department of Intensive-and Perioperative Care, Ska˚ne University Hospital; Department of Clinical Sciences Lund University, Lund, Sweden. 3 Duke University Medical Center, Durham, North Carolina. 4 Department of Cardiology, Lund University, Skane University Hospital, Lund, Sweden. *This panel discussion was held at Chilling at the Beach: Therapeutic Hypothermia and Temperature Management, Current and Future, on Friday, Feb. 25, 2011 in Miami, Florida. 2

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124 that you do clinical examination every day, so a patient with brain edema needs deep sedation. My question was, do we do clinical examination, neurological examination, whether you wake them up or not? Dr. Friberg: Yes, we assess neurological function and perform an extended neurological investigation in all patients at least once daily, whether they are sedated or not. By the way, all our patients are sedated during the treatment intervention, and longer if necessary. We are actually writing a paper in which we describe 4 patients who developed brain edema among our first 200 patients and who were eventually declared brain dead. All four were young patients with prolonged time to return of spontaneous circulation. In these four cases, it was quite clear that something was fundamentally wrong since the initial recovery of brain stem reflexes was followed by a subsequent loss. These cases emphasize the importance of repeated neurological examinations in the ICU.

EXPERT PANEL DISCUSSION massive and long, and so in a way, you know, we have a lot more to learn. The challenge here is if you wanted to go through all these various steps and permutations, it would be several years before we could actually understand it, and in some cases, it is very hard to do that in patients. We have pig models, but as David points out, and very rightly, we really don’t know how well these various models really represent what we do. Why do we think 24 hours is optimal for brain salvage? Is there much data to suggest that 24 is better than 48? Or is it possible that more severe brain injury should be treated longer?

Question: But you risk increased intracranial pressure by waking them up. Is it not true?

Dr. Erlinge: We have no idea. We are in the same boat. We do know that if you delay the onset of cooling, longer, the less cardioprotective effect you get. I think there is one big difference between brain reperfusion and heart reperfusion. For brain reperfusion, you know that you get an effect even if you come in after reperfusion. We know from the heart that we have no effect whatsoever of cooling if we come in after reperfusion. So that kind of indicates that after reperfusion, cooling is not so important for the heart, but it is obvious that it is important for the brain.

Dr. Friberg: I don’t think any of the patients, actually none of them, developed significant brain edema during hypothermia treatment. It developed after having been rewarmed, and this is also when we reduce sedation to wake them up. I agree with the potential problem that you have identified, but fortunately, significant brain edema seems to be uncommon after cardiac arrest and was quite evident when it occurred in our four young patients.

Question: My question to Professor Erlinge. This means the reason for the short duration of the MRI is just a technical issue or the mechanics of having the mission be rated and able to get the catheter out. Not about changing the location of the femoral vein and the patient mobilize in ICU. This is when you are cooling him for longer, close to the brain, at the same time getting him mobilized. We have people walking around in CCU after PCI as soon as they can.

Question: Let’s discuss hypothermia as treatment for myocardial infarction. In regards to the economics of the catheter laboratory, I’m a little concerned. Many years ago, we reported that relatively brief periods of hypothermia only delay eventual cell death, and that indicated that we need to cool longer. So David, you propose to treat myocardial infarction using relatively brief cooling periods? Do you think that before you start the next clinical study, you have enough preclinical studies assessing long-term outcome? This was actually emphasized in the last presentation. Is this a longterm beneficial effect, or again, are you just delaying the eventual outcome? You showed those speckled appearances of the myocardium using MRI. If there’s tissue inflammation, then potentially those viable areas may ultimately die because of secondary inflammatory cascades.

Dr. Erlinge: Walking around at 33. It might be possible, I think. But I think the strongest rationale was that when we did the RAPID MI-ICE trial, I saw these patients lying immobilized and sedated for 6 hours, and I’m used to seeing the heart infarction patients and they are up very early after the treatment. We had converted this patient group, which is an enormous group, into an ICU case. Maybe you can do the math for the United States, if we should convert every myocardial infarction into an ICU case then with necessary of intensive care. It would be so expensive. Comment: It maybe could be worth it. But it’s very expensive.

Dr. Erlinge: Yes, of course, the concerns are real and maybe we are wrong. But it seems that for the heart, things happen much quicker than for the brain. The reperfusion period is much shorter. We have only done one series of pig experiments, and those were sedated pigs, so they are not the same as an awake human. From our experience in the catheter lab, we know that the patient often crashes after/during reperfusion due to the reperfusion events. That period is over after an hour or something like that. So it looks like it’s a relatively brief vulnerable period, but of course only the clinical trial can answer the question.

Comment: The data suggests that there may be a benefit for the patient in cardiogenic shock or congestive heart failure. Right now, most centers actually exclude patients who need either mechanical support or multiple drugs from getting hypothermia after cardiac arrest. And I’m not sure whether the Target Temperature Management (TTM) study that is being done, the 36 versus 33, is going to actually exclude patients in cardiogenic shock from the hypothermia trial. But should that not be a group that is either included or analyzed separately, or if it’s so good for the heart, why are we excluding these patients from getting hypothermia? Because I know at our institution, we do exclude them if they are on multiple pressors, particularly if they had an initial nonshockable rhythm. A question for the group.

Comment: I think this is particularly hard. If hypothermia was a drug, you would actually test the duration, the depth of the dose. You would test different age groups. The variables are

Dr. Ohman: Obviously, I don’t have good answers for you here. But my take on this is that this is a rapidly evolving field. Let’s just be sort of pragmatic here for a second. Cardiac shock

EXPERT PANEL DISCUSSION is actually to some extent a clinical diagnosis, and so essentially most patients are intubated and on pressors. It is actually very hard to make that diagnosis until you put in the Swan catheter or do something invasively so that you could understand it. Yes, we do see pulmonary edema on chest Xrays as sort of one indication potentially, but the reality is that patients with a pulmonary edema sometimes have a noncardiac pulmonary edema too. So we are challenged to make the right diagnosis. So I wouldn’t actually feel very strongly either including them or excluding them, per se. But I think as the data from Abbot Northwestern suggests, the outcomes in this group of patients are not as good. I mean, you are talking cardiac arrest and cardiogenic shock. And the predicted outcome in that patient if you did nothing is almost 100% mortality, so I don’t have a good answer, maybe others do. Dr. Friberg: I could comment on it. Actually, I don’t know the rationale for not including patients in cardiogenic shock to treatment with hypothermia or temperature control. In the TTM trial for example, we do not exclude patients with cardiogenic shock. But shock must be reversed prior to randomization, which can only be done if the patient is brought to the cath lab. Comment: I might say it’s really just a leftover from the design of the Hypothermia After Cardiac Arrest (HACA) trial, in which they wanted to exclude those patients in order not to make the population too heterogenous. I agree with Hans. I think there is really no reason we shouldn’t include those patients in the ongoing trials. Comment: Regarding the HACA trial, for example, they only included 8% of all patients that were screened. That’s why the HACA trial really has very low generalizability. Question: I have a question regarding the timing of your evaluation in terms of prognostication at five days after the arrest. So you said 72 hours after normothermia. My question is, as SSEP remains a very powerful prognostication tool, what’s the timing regarding SSEP? I believe it should be performed at 72 hours? So do you shave your time for the SSEP, or do you keep it at 72 hours from the return of spontaneous circulation (ROSC)? Dr. Friberg: In the protocol for the Lund Coma Project, the idea was to evaluate SSEP at 72 hours after normothermia. And this will also be done in the TTM trial; we chose the same time. I know there are other studies in which you evaluate SSEP at an earlier time, and SSEP seems to be a very good predictor even at 24 hours after arrest. However, the sensitivity is disturbingly low, which limits its value. Comment: I’m from Abbott Northwestern, where you presented some of those slides. I take care of a lot of the cooled cardiac arrest patients, and there is a large percentage of cardiogenic shock patients that we take care of. My comment is that they should not be excluded. They were very easy to take care of during that time period of hypothermia. That is when the arrhythmias are settled down, that sort of low SVR state. That is the easiest time to take care of these patients. You can put on a temporary pacemaker if you need it during that time period, which, you know, people have been afraid to do. Does that work in hypothermia? Absolutely, it works. So you go

125 through that time period, and it’s during the rewarming period when you develop cardiogenic shock. What we’ve noticed as ICU doctors is that when patients are not hypothermic, that’s when you sometimes see them develop cardiogenic shock. It is much harder to manage than the patients who get hypothermia treatment. So, patients in shock shouldn’t be excluded, at least from my experience. We’ve treated over 200 now. Dr. Ohman: I’m glad I did some justice to your data, because it’s pretty impressive. Although, when you look at the cardiogenic shock population on its own, it may be less impressive, but then again, that is a very high risk, too. I just want to make sure, I didn’t make this comment in my talk and that gets back to some of the prior comments. You really cannot give a patient with cardiogenic shock two liters of ice cold saline. That is a serious problem. So when we talk about treating cardiogenic shock in the setting of cardiac arrest, we are talking about topical cooling or endovascular cooling, but not IV fluid cooling. That is very important to understand, because some of your protocols actually use IV fluids—ice cold IV fluids— which is very acceptable to bring down the temperature, but that might be very difficult in a cardiogenic shock patient. Question: In this conference, we’ve talked a little bit about hyperthermia and its detrimental effects. Do we have that concern in myocardial infarction? Have you measured heart temperature? Dr. Erlinge: Animal studies have shown that increased temperature up to 39 C increased the infarct development. We tried to look at our ST-elevation myocardial infarction (STEMI) patients from previous years to see if spontaneous temperature at arrival correlated with troponin-levels or outcome to see if low temperature would be protective. But it didn’t give us anything, because patients coming in with very low temperature are often very sick patients with long transportation times, so it was very difficult to get any conclusive data from that. Comment: The only thing to add to that is that there is some anecdotal evidence of patients with high white cell count, indicating maybe fever from another cause, have worse prognosis. But again, that’s different from the temperature component, so it’s hard to separate those out. Question: Okay, Professor Friberg, you said in the Lund Coma Project that there is a certain number, 30% or so, that develop electrographic epileptic seizures. All of us will know that status epilepticus may become refractory even to barbiturates. One of the options would be to reinstitute hypothermia. Did you do that in any of your patients, and if yes, how did he or she respond, electrophysiologically? Dr. Friberg: That’s a very interesting question. We did not do it in any of our patients, but I talked to Dr. Graffagnino about it, and maybe Dr. Graffagnino could give us comment. Have you seen patients who begin to develop clinical seizures during rewarming? And have you treated them by reinstituting cooling? Dr. Graffagnino: Some of the debate is that these changes didn’t look like a seizure. With the epilepsy people, we argue every day about what you call a seizure and the semantics of eletrographic seizures. But if we assume that it’s an electrical

126 abnormality, when we see those, we’ve actually asked our colleagues to go back a half degree or a degree, and the abnormalities disappear. And then at that point, we load them up with valproic acid or phosphenitoin or levitor aciditam, or we’ll put them on propofol and get their therapeutic drug levels up. Then once they’ve settled down, we’ll go back to the .2 or .3 degree per hour rewarming phase, and they come back again. So we’ve done this anecdotally maybe 3 to 6 times in the last year, and every time it seems like once they develop true electroconvulsive seizures, those become much more difficult to treat with temperatures. So what we’ve found is that treating the first signs of seizure activity before they evolve into whole screen abnormalities seems to be therapeutic, and it may be a sign that the brain wasn’t quite ready for all of that activity. But we’ve never systematically studied this. These are just anecdotes. Comment: My comment was one about the business case of hypothermia. We have done some white paper research and looked at how you make the business case for hypothermia in our organization. We’ve actually been able to change our billing structure, and we bill for hypothermia patients in the coronary care unit on an hourly basis instead of the traditional midnight census way. It has actually proven beneficial for our organization and to push hypothermia a little quicker with our administration using a specific cooling revenue code. Has anybody else seen success with that? Question: In regard to the study that you are planning to do post-MI, you are going to start cooling the patient just before reperfusion. Are you planning to stop the cooling an hour after or just before you move the patient out? Is it safe for the brain to rewarm the patient that fast? How can we wait 6 to 12 hours? In this study, we are planning to rewarm them and send them to the CCU. Dr. Erlinge: Well, these are patients with just a mild indication of myocardial infarction. They have had no cardiac arrest, and they are awake all the time. So the brain should be no problem. They have an intact brain when they come in. The seizures should not be any problem. I mean, we are not actively warming them up. Their temperature will spontaneously go up. So it will take some time anyway. I don’t think there is a major concern. I am not a neurologist, but I don’t think it’s a major problem with seizures during rewarming if the brain is unharmed. Comment: In the Cool Aid trial, we really didn’t specifically follow the patient systematically for detailed neurological assessment. But in terms of gross things like seizures, we really didn’t see any concerns of value to the cooling in those awake sedated patients. Question: At your institutions, are the cardiologists and neurologists speaking? Response: When they have an interpreter, and that is the critical care doctor. Comment: I think you’ll find as long as the cardiologists read the ECG and not EEG and vice versa, I think we’re in great shape. Final: Thank you all for this very rich and informative discussion.

EXPERT PANEL DISCUSSION Key References from Panel Participants Cronberg T, Lilja G, Rundgren M, Friberg H, Widner H. Longterm neurological outcome after cardiac arrest and therapeutic hypothermia. Resuscitation 2009;80:1119–1123. Cronberg T, Rundgren M, Westhall E, Englund E, Siemund R, Rose´n I, Widner H, Friberg H. Neuron-specific enolase correlates with other prognostic markers after cardiac arrest. Neurology Jul 20, 2011. [Epub ahead of print; DOI: 10.1212/ WNL.0b013e31822a276d] Dixon SR, Whitbourn RJ, Dae MW, Grube E, Sherman W, Schaer GL, Jenkins JS, Baim DS, Gibbons RJ, Kuntz RE, Popma JJ, Nguyen TT, O’Neill WW. Induction of mild systemic hypothermia with endovascular cooling during primary percutaneous coronary intervention for acute myocardial infarction. J Am Coll Cardiol 2002;40:1928–1934. Fitzgerald P, Goodacre SW, Cross E, Dixon S. Cost-effectiveness of point-of-care biomarker assessment for suspected myocardial infarction: the randomized assessment of treatment using panel Assay of cardiac markers (RATPAC) trial. Acad Emerg Med 2011;18:488–495. Go¨tberg M, Olivecrona GK, Koul S, Carlsson M, Engblom H, Ugander M, van der Pals J, Algotsson L, Arheden H, Erlinge D. A pilot study of rapid cooling by cold saline and endovascular cooling before reperfusion in patients with STelevation myocardial infarction. Circ Cardiovasc Interv 2010;3:400–407. Go¨tberg M, van der Pals J, Go¨tberg M, Olivecrona GK, Kanski M, Koul S, Otto A, Engblom H, Ugander M, Arheden H, Erlinge D. Optimal timing of hypothermia in relation to myocardial reperfusion. Basic Res Cardiol 2011;106:697–708. Go¨tberg M, van der Pals J, Olivecrona GK, Go¨tberg M, Koul S, Erlinge D. Mild hypothermia reduces acute mortality and improves hemodynamic outcome in a cardiogenic shock pig model. Resuscitation 2010;81:1190–1196. Mehta RH, O’Shea JC, Stebbins AL, Granger CB, Armstrong PW, White HD, Topol EJ, Califf RM, Ohman EM. Association of mortality with years of education in patients with ST-segment elevation myocardial infarction treated with fibrinolysis. J Am Coll Cardiol 2011;57:138–146. Nielsen N, Friberg H. Insights from the evidence evaluation process—do we have the answers for therapeutic hypothermia? Resuscitation 2011;82:501–502. Nielsen N, Friberg H, Gluud C, Herlitz J, Wetterslev J. Hypothermia after cardiac arrest should be further evaluated—a systematic review of randomised trials with meta-analysis and trial sequential analysis. Int J Cardiol Jun 29, 2010. [Epub ahead of print; DOI: 10.1016/j.ijcard.2010.06.008] Nielsen N, Hovdenes J, Nilsson F, Rubertsson S, Stammet P, Sunde K, Valsson F, Wanscher M, Friberg H; Hypothermia Network. Outcome, timing and adverse events in therapeutic hypothermia after out-of-hospital cardiac arrest. Acta Anaesthesiol Scand 2009;53:926–934. Nielsen N, Sunde K, Hovdenes J, Riker RR, Rubertsson S, Stammet P, Nilsson F, Friberg H; Hypothermia Network. Adverse events and their relation to mortality in out-of-hospital cardiac arrest patients treated with therapeutic hypothermia. Crit Care Med 2011;39:57–64. Patel MR, Thiele H, Smalling RW, Chandra P, Zhou Y, Cohen M, Perera D, Ohman EM. A multicenter, randomized, controlled study of mechanical left ventricular unloading with counterpulsation to reduce infarct size prepercutaneous coronary intervention for acute myocardial infarction: rationale and design of the Counterpulsation Reduces Infarct Size Acute Myocardial Infarction trial. Am Heart J 2011;162:47–55.e1.

EXPERT PANEL DISCUSSION Rizik DG, Klassen KJ, Dowler DA, Villegas BJ, Dixon SR. Promising though not yet proven: emerging strategies to promote myocardial salvage. Catheter Cardiovasc Interv 2006;68:596–606. Rundgren M, Westhall E, Cronberg T, Rose´n I, Friberg H. Amplitude integrated EEG (aEEG) can predict outcome after cardiac arrest. Crit Care Med. 2010;38(9):1838–1844. Unverzagt S, Machemer MT, Solms A, Thiele H, Burkhoff D, Seyfarth M, de Waha A, Ohman EM, Buerke M, Haerting J, Werdan K, Prondzinsky R. Intra-aortic balloon pump counterpulsation (IABP) for myocardial infarction complicated by cardiogenic shock. Cochrane Database Syst Rev 2011;(7): CD007398. van der Pals J, Go¨tberg MI, Go¨tberg M, Hulte´n LM, Magnusson M, Jern S, Erlinge D. Hypothermia in cardiogenic shock re-

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Developing clinical trial in acute myocardial infarction.

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