THERAPEUTIC HYPOTHERMIA AND TEMPERATURE MANAGEMENT Volume 2, Number 1, 2012 ª Mary Ann Liebert, Inc. DOI: 10.1089/ther.2012.1502

Therapeutic Hypothermia and Post-Cardiac Arrest Moderator: Carmelo Graffagnino, M.D.1 Participants: Eyal Herzog, M.D.,2 Justin Lundbye, M.D.,3 and Hans-Joerg Busch, M.D. 4

Previous clinical studies have demonstrated the beneficial effects of early cooling in cardiac arrest patients. Two landmark studies in 2002 demonstrated that the use of therapeutic hypothermia after cardiac arrest decreased mortality and improved neurological outcome. This has led to the International Liaison Committee on Resuscitation and the American Heart Association to recommend the use of therapeutic hypothermia after cardiac arrest. A series of state-of-the-art lectures presented at the 2011 Therapeutic Hypothermia and Temperature Management Meeting in Miami brought together four outstanding speakers to discuss this topic. This series of presentations concentrated on the use of therapeutic hypothermia in patient populations and reviewed comprehensive strategies for the management of survivors out of hospital cardiac arrest. A current controversy is over exactly which patients would benefit from cooling and which would not. Dr. Justin Lundbye, Hartford Hospital, discussed inclusion/exclusion criteria, as well as methodologies, including surface and endovascular cooling approaches. Inclusions include therapeutic hypothermia being a Class 1 recommendation for survivors of cardiac arrest with other patient populations including in-hospital and non-shockable rhythms being considered for this potential beneficial therapy. Dr. Eyal Herzog from Columbia University College of Physicians and Surgeons discussed hurdles in terms of implementation of cooling programs. These include development of focused treatment guidelines based on available published research, as well as printed standardized hospital admission and discharge order sets. Development of educational curriculum for all healthcare providers, as well as integrated computer databases to help collect data and assess patient outcome, is helpful to move this treatment modality forward. Individual case reports were also described that indicate conditions by which post-resuscitation care and hypothermia appear to be beneficial. Dr. Hans-Joerg Busch from University of Freiburg summarized several clinical trials using hypothermia to treat cardiac patients. Specifically a new intra-arrest transnasal cooling approach appears to be safe and feasible in cardiac arrest patients. Dr. Carmelo Graffagrino from Duke Medical Center summarized the important data on dosing beyond the clock. This presentation discussed the timing, depth, and duration of cooling after cardiac arrest. The following is a summary of the discussion that followed the individual lectures. A large number of answers and opinions added to the rich discussion that was appreciated during this hypothermia meeting.

Question: I have question that I would like to open up to the panel, particularly with respect to the care of postarrest patients. Let’s assume you get your patient back. We know from preclinical work, again from the Safar Institute, that there is a kind of a biphasic phase of no-flow during CPR, with low perfusion during that first 1–2 hours post arrest where the work shows that hyperoxia is harmful. In fact, hypertension may be harmful because there is this hyperperfusion phase that may last a couple hours. But then between 2 and 24 hours, there seems to be a relative no-flow or hypoflow phenomenon in the brain that we are currently not monitoring because we are not putting devices in these patients’ brains. We are not monitoring biochemistry without monitoring PO2. We are not looking at cerebral blood flow. So when you guys determine your goals from mean arterial pressure, and your goals from ventilator management, particularly since CO2 has such an effect on brain perfusion, my questions to the panel are, what is your target for MAP so you are balancing and not hurting the heart and keeping the brain perfused? And do you alpha or pH that control? Do you attempt control of your ventilation parameters or do you just do them at room temperature? How do manage your ventilator or your perfusion in your cold patients? Dr. Hans-Joerg Busch: You’re absolutely right, and it’s a big challenge. We turn off any heating modality for ventilation if that’s what you were asking. But then we set our FiO2 to meet a saturation between 94% and 98% and keep it at that. In fact, we have gone out to EMS and really advocated for them to reduce it as much as they can at that time. In reference to the mean arterial pressure, we really just follow the neurosurgical literature in trying to keep the mean arterial pressure of 70 mmHg and even some higher is recommended in some literature up to 100 mmHg. It really depends on what the past physiology is. If the patient has congestive heart failure, we would probably use more of a beta agonist to facilitate the contractility. We’ll often have a swan catheter in place to really measure what’s going on because you know after resuscitation, we can see a transient drop in SVR at times. So we’re really sort of trying to tune it according to a patient’s underlying disease.


Department of Medicine/Neurology, Duke University, Durham, North Carolina. St. Luke’s-Roosevelt Hospital Center, Columbia University College of Physicians and Surgeons, New York, New York. 3 University of Connecticut School of Medicine, Hartford Hospital, Hartford, Connecticut. 4 Universita¨tsklinikum Freiburg, Internistische Intensivstation Heilmeyer, 79106 Freiburg, Germany. 2


EXPERT PANEL DISCUSSION Comment: I think I agree with you. We have to define between the group of patients who has an acute coma syndrome and the patients who are primary cardiomyopathy. Traditionally, I know that you are not a biologist, but I am defining between two groups of patients who may survive a cardiac arrest where the acute coronary syndrome (ACS) patient will be the majority. When you have an ACS patient, you have to maintain coronary perfusion because you just put a stent in the LAD, you have to give us a starting blood pressure. If you have a patient with chronic heart failure who lives at home with a blood pressure of 70 or 80 and a cardiac arrest, he does not need to achieve this high blood pressure because he does not live in this blood pressure. He lives with a much lower blood pressure. You can make it even simpler: don’t use mean pressure, use systolic blood pressure in this situation. So I would say for the heart population, 80 mmHg of systolic blood pressure would be acceptable for the heart. Dr. Hans-Joerg Busch: I think it’s a problem. We know from the neurointensive care that in patients with mild brain edema, the intracranial pressure will increase about 10– 20 mmHg. When you have a MAP about 80–90 mmHg, patients have a resulting cerebral perfusion pressure of 70 mmHg (CPP = MAP - ICP). But if CPP falls under 70 mmHg, cerebral damage and severe perfusion problems can occur. For that, we try to go over 80 mmHg. For instance, when the patient has some kind of extracerebral vascular stenosis, we go over 90 mmHg. Additionally, when the patient suffers from heart failure or cardiogenic shock, we try to go on mechanical device support for the heart. For the mechanical device, our experience is that the NSE is always high and you can’t use this biomarker because of hemolysis. Question: I want to ask you a question because I was shocked by your 35% survival of pulseless electrical activity (PEA). I’m presenting in the ACC completely contradictory findings. Can you tell me how you get 34% survival from volunteer ambulance service (VAS) history? Answer: So we use the percenting rhythm, right? So if it’s PEA and they convert to ventricular fibrillation (VF), it’s still PEA. Is that what you’re asking? Answer: Yes. Comment: The same thing for in-hospital cardiac arrest, if it’s the percenting rhythm. We use the first rhythm that we come upon when we resuscitate that patient. I suspect a lot of the survival that we see is because we were able to look at down time as an exclusion criteria. I’m not sure if you’ve done that when you look at your data, but I think it’s extremely important. If you left these patients in, and I’m not saying we shouldn’t cool them, but if you let them into your study with a 35-minute down time, your numbers are not going to be as convincing. I’m not suggesting that you shouldn’t cool these patients necessarily, I’m just suggesting from a pure reporting standpoint regarding the benefits of hypothermia on this patient population, you really need to take that into consideration.

7 Dr. Hans-Joerg Busch: In our registry, we see patients with asystolye as the presenting first rhythm long down time and a long cardiopulmonary resuscitation (CPR) time. But also in this case patients benefit from therapeutic hypothermia. Comment: Yes, we have the same experience that you nicely addressed. I think down time versus quality of CPR is really the issue to discuss. Down time can be long if you have good CPR. You know, we have in the hypothermia registry more than 3000 patients. If you look at those data, you can see that patients with long down times, down times of 45 minutes or more, still survive. A significant number of them survive with a good outcome. And if you look at the records, you can see that it’s to do with the quality of the CPR. You should maybe not focus so much on that, more on the quality of CPR, I would say. Comment: I want to second that. As part of my other jobs, I get to go out and play in the streets and chase down the ambulances and help run codes. I find when I go there, even if there are four or five first responders, my primary job isn’t helping the paramedics. They know what to do. My primary job is working with the first responders saying, push harder, push faster, your CPR isn’t good; you’re getting tired. The next person takes over. I strongly encourage you to work with your emergency medical services (EMS) to do one of two things. First, investigate automated CPR devices because in some of our service areas where they have started to use these, we are starting to see better perfusion and better outcomes. Alternatively, utilize cardiac monitors that provide a feedback algorithm that will tell the first responder, the person doing compressions, that they are pushing hard enough and they are pushing fast enough. Because, if you can’t measure, you can’t change, and that’s one of the things we’ve been working on strongly with making sure that the quality of the CPR is calculated at a good level. Question: Carmelo, I have a question. I like your idea of titrating to a biological marker of when to stop cooling, but the data you cited are Fred Colbourne’s data, and they were able to show, again using the clock, that longer ischemic times needed longer cooling times. Since not every medical center is going to have all of the modern equipment that might be necessary like continuous EEG recording, can you foresee deriving an algorithm using physiologic monitoring that could tell us what to do for a certain duration of ischemia and cool for a certain amount of time? Dr. Carmelo Graffagnino: The technology issues are twofold. One, the best data are actually very intriguing because the bisque can give you bifrontal, actual continuous EEGs. When I go to see a patient in the CCU and while I’m waiting for us to hook him up, I just put the vest monitor on and look at the bifrontal source data. I think what we need is actually research that supports analysis of EEG data. Those can be randomized, so perhaps a pilot study where we are looking at data with biochemistry and EEG. Currently, EEG monitoring can be done without technicians. Comment: We’re working with brain net that is actually put on by our ICU nurses, and we did a clinical trial comparing nurse applied EEG to technician applied EEG. Six electro-

8 cephalographers couldn’t tell the difference. So the kind of technology that we are working now is wireless. This is actually one that any CCU can have and just invest in wireless data for us to look at 200 miles away. These EEG leads can be put on the head with needles and bilateral strips, and there are different versions of this technology. This may give us a very quick EEG data in the ER and, you know, 20 minutes later, the data, because it’s not a complicated algorithm that we’re looking at, may be interpretable. I think it’s got to be backed up by studies that actually show that once we have these data, having all the diagnostics doesn’t help if an intervention didn’t make a difference. So, I think the first step is to prove that the physiology is predictive of the outcomes and then show whether the physiology can be altered. I think that’s probably the next 4–5 years’ worth of work. Dr. W. Dalton Dietrich: Investigators are assessing the molecular mechanisms of learning and memory that are altered after ischemic and traumatic brain injury. My question is, in these cooled post-cardiac patients that appear to do better in terms of their early outcomes, are there long-term cognitive assessments being conducted to see if actually they are benefitting in more ways than just maybe some very crude neurological assessment strategies? Response: That’s a very good point because there was a paper recently looking at subarachnoid hemorrhage patients and looking at those that have a Glasgow Coma Scale (GCS) of 4 and 5, they were just like normal people. Even though they say they were normal, they weren’t returning back to work and had severe neurocognitive impairments when assessed. We’ve also seen this in the bypass literature where you can’t look at stroke as your only outcome, you have to also assess neurocognitive changes. That’s where in the neurocognitive part starts adding to this, it may be that patients who localize and have a GCS of 10 still do very poorly. As, you know, the ranking isn’t reflecting what is really going on. The GCS score is less valid as far as interventions, and there are not cognitive outcomes. Response: What’s been our failure, too, I think, is to really ensure that when the patient goes home, there is a structure in place to have them follow-up with neuropsychology testing or rehabilitation or someone that can really ensure that this is in place. So, yeah, we don’t really have anything. Dr. W. Dalton Dietrich: I guess another question has to do with status epilepticus. Recent studies indicate that early cooling after traumatic brain injury reduces the incidence of post-traumatic epilepsy. I think I heard you say that maybe intraischemic cooling seemed to have a benefit in terms of reducing epilepsy after cardiac arrest. Is that being looked at currently? Again, is that an important outcome measure to assess in terms of recovery of function? Answer: I haven’t seen any literature looking at long-term epilepsy following anoxic damage with hypothermia as a treatment. I know anecdotally that most of the early seizures we see are just a measure of severe brain injury. But the ones that develop late in the hypothermia treatment period or during rewarming are modifiable by temperature alterations and when we’ve gone down a degree, those seizures almost

EXPERT PANEL DISCUSSION stop. We can add our anti-convulsants, get ’em loaded up and then gradually rewarm again and see where they are now because we don’t preemptively use anti-convulsants. Which anti-convulsant to use is also debatable because phenytoin is actually neurotoxic. Thus, although it can stop seizures, phenytoin may hurt the brain. So we haven’t even chosen the right anti-convulsant to use if you’re going to treat them. There is a paper just in this month’s Neurocritical Care Journal where they looked at the largest series patients, with diffusion-weighted imaging. They did multiple time points and found that if you had hippocampal and bifrontal cortical diffusion weighted abnormalities at baseline, those seem to be predictive of outcome. But there were not enough data because some of the abnormalities resolved and cleared up so they were transient changes. It’s probably very difficult to get these cooled patients scanned. If you are going to use MR results to decide when to rewarm, that’s not practical. To use it for prognostication, the clinical and electrical features are more highly predictive unless you see laminar necrosis everywhere. If you see laminar necrosis, you probably have a nonreactive EEG and probably have a GCS that is less than five anyway, so I think the MR is just showing you what you already see. One of the things that people are starting to look at in trauma is a Diffusion Tensor MR to assess white matter tracts. I think that’s all investigational at this time. Question: I think we are all in agreement that we are looking at starting cooling as quickly as possible. I’m very much a fan of bringing it into the pre-hospital setting. From the panel, what are your thoughts about intra-arrest cooling by starting cold saline during the arrest? This is a controversial issue, but I think that it’s one question that I’d sort of like to walk away from this meeting with some people’s feelings on this topic. Answer: It is very controversial. In New York, our EMS people infused cold saline and our hospital specialist really did not like it. So this is very controversial now. You have to discuss and not take one person’s opinion. So you have to find the right dosing for how much fluid you can give because most of these patients will have significant heart failure. So you may not want to give them 2 liters of cold saline. I think that the question of dosing is very important. But I also think early administration of cold saline may be beneficial. The question I do not know the answer to is how much. Comment: The question is, I think, do you want to cool intraarrest or do you want cool post-arrest. If you want intraarrest, I think cold saline is not a good idea from the fact of physiology because you put into the intravenous system 1 or 2 liters. We know that we have to bring the heart to a normal size to have a good defibrillation rate. Dr. Hans-Joerg Busch: I think the issue is if you introduce cooling by the EMS. I also am a big believer in early cooling, but introducing it to the EMS. My concern is that you are throwing in too many variables, and I’m not sure if that is the right place to do it. We have not taken up the practice of initiating cardiac arrest induction of hypothermia in the hospital just because I don’t think the data are really there yet in either direction. But I am a believer as soon as you get ROSC, you should really be very aggressive in cooling them.

EXPERT PANEL DISCUSSION Comment: My understanding as a non-cardiologist is that high volume, cold fluid, particularly high volume fluid pre-ROSC, actually impedes return to the coronary sinuses, and that may therefore affect the likelihood of getting ROSC. To counter that, I don’t think it’s the temperature of what you’re doing giving to the heart, I think it’s the high volume fluid. That was the rationale when they looked at the transnasal cooling; they compared ROSC with cooling the brain and the body through fluorocarbon cooling of the head versus doing it with saline. They were getting much higher ROSC rates with systemic cooling than observed with high-volume fluids. To counter that, the capture group in Richmond has actually been cooling all their patients pre-ROSC. The last conversation I had, looking at their ROSC grades, they thought they were actually higher than their historical rates. For the paramedics, it is actually not difficult to initiate a saline infusion in these patients. Question: How old a patient can we do a hypothermia therapy? I have to decide about them next time. So if you have experience or exclusion criteria, please tell me. Answer: In our experience, we involve patients who are 18 or above. The youngest we enrolled was age 22. The oldest we enrolled was age 95. The other survivor we had is now 95, and was cooled when he was 92–93. So age is not a limit, I believe. Comment: Yes, I agree. In our published paper from the registry data on about 1000 patients, we did find that age was an independent risk factor for poor outcome. We have no upper or lower age limits actually in our center and in our region. But that is, of course, up to each center to decide. Key References from Panel Participants Al-Senani FM, Graffagnino C, Grotta JC, Saiki R, Wood D, Chung W, Palmer G, Collins KA. A prospective, multicenter pilot study to evaluate the feasibility and safety of using the CoolGard System and Icy catheter following cardiac arrest. Resuscitation 2004;62:143–150.

9 Aziz EF, Pratap B, De Benedetti Zunino ME, Tormey D, Javed F, Frankenberger O, Hong MK, Herzog E. Success in implementing a hospital-wide evidence-based clinical pathways system for the management of cardiac patients: the ACAP program experience. Crit Pathw Cardiol 2011;10:22–28. Busch HJ, Eichwede F, Fo¨disch M, Taccone FS, Wo¨bker G, Schwab T, Hopf HB, Tonner P, Hachimi-Idrissi S, Martens P, Fritz H, Bode Ch, Vincent JL, Inderbitzen B, Barbut D, Sterz F, Janata A. Safety and feasibility of nasopharyngeal evaporative cooling in the emergency department setting in survivors of cardiac arrest. Resuscitation 2010;81:943–949. Castre´n M, Nordberg P, Svensson L, Taccone F, Vincent JL, Desruelles D, Eichwede F, Mols P, Schwab T, Vergnion M, Storm C, Pesenti A, Pachl J, Gue´risse F, Elste T, Roessler M, Fritz H, Durnez P, Busch HJ, Inderbitzen B, Barbut D. NTRA-arrest transnasal evaporative cooling: a randomized, prehospital, multicenter study (PRINCE: Pre-ROSC IntraNasal Cooling Effectiveness). Circulation 2010;122:729– 736. Fink K, Schwab T, Bode C, Busch HJ. Endovascular or surface cooling?: therapeutic hypothermia after cardiac arrest. Anaesthetist 2008;57:1155–1160. Herzog E, Javed F. Primary prevention of myocardial infarction: putting the evidence to use. Arch Intern Med 2010;170:1381– 1382. Herzog E, Shapiro J, Aziz EF, Chong J, Hong MK, Wiener D, Lee R, Janis G, Azrieli Y, Velazquez B, Lacdao L, Mittal S. Pathway for the management of survivors of out-of-hospital cardiac arrest. Crit Pathw Cardiol 2010;9:49–54. Rai M, Lundbye JB. Successful use of therapeutic mild hypothermia after cardiac arrest. J Cardiovasc Med (Hagerstown). 2010 [Epub ahead of print]. Schwab S, Georgiadis D, Berrouschot J, Schellinger PD, Graffagnino C, Mayer SA. Feasibility and safety of moderate hypothermia after massive hemispheric infarction. Stroke 2001;32:2033–2035. Schwarz M, Krueger MW, Busch HJ, Benk C, Heilmann C. Model-based assessment of tissue perfusion and temperature in deep hypothermic patients. IEEE Trans Biomed Eng 2010;57:1577–1586.

Therapeutic hypothermia and post-cardiac arrest.

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