THERAPEUTIC HYPOTHERMIA AND TEMPERATURE MANAGEMENT Volume 4, Number 2, 2014 ª Mary Ann Liebert, Inc. DOI: 10.1089/ther.2014.1504
Expert Panel Discussions
Temperature Management in Neurological and Neurosurgical Intensive Care Units Moderator: David Erlinge, MD, PhD1 Participants: Kees Polderman, MD, PhD,2 Kelley Lockhart, MD,3 and Neeraj Badjatia, MD 4
The use of temperature management in neurological and neurosurgical intensive care units (ICU) has gained acceptance and resulted in better outcomes in some patient populations. In various studies of out-of-hospital cardiac arrest as well as traumatic brain injury, directed temperature management protocols in the ICU have led to reductions in periods of reactive hyperthermia that occur in many patients with severe injuries. In addition, lowering the temperature to various levels of hypothermia also appears to reduce secondary injury mechanisms, intracranial pressure levels, and edema formation. Nevertheless, controversies exist in what patient population we should cool and what level of cooling is most appropriate in neurological settings. A series of stateof-the-art lectures presented at the 2014 Therapeutic Hypothermia and Temperature Management meeting in Miami brought together experts in the field of therapeutic hypothermia and temperature management strategies to discuss this important topic. Dr. Kees Polderman, Department of Critical Care, University of Pittsburgh School of Medicine, Pittsburgh, PA, provided new information regarding the reasons to cool patients and new strategies for cooling awake patients, which is an important clinical question. In the awake state, patients shiver and this can produce barriers to reducing temperature effectively and making the patient comfortable. Dr. Kelley Lockhart, Department of Internal Medicine, Abbott Northwestern Hospital, Minneapolis, MN, emphasized the potentially detrimental effects of fever in various patient populations, including subarachnoid hemorrhage. In these patients specifically, 70% develop fever during the first 10 days. Although it is difficult to determine causes underlying elevations in temperature, hyperthermia continues to be a risk factor that may be controlled by targeted temperature management. Dr. Neeraj Badjatia, Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, described novel approaches to monitor degrees of shivering in patient populations. Continuing studies are directed toward understanding the clinical relevance of shivering as well as antishivering strategies that may allow cooling to be introduced in the awake subject. 1
Department Department Department 4 Department 2 3
of of of of
It is clear that as therapeutic hypothermia and temperature management strategies are increasingly used by many caregivers, these types of questions are becoming more and more important to define and provide suitable strategies for better outcomes. Question: Two questions. First, you showed some slides containing data on magnesium that was not supportive of your thesis, and I wonder if you could speak a little bit more rigorously about the data that prove whether or not magnesium is part of the protocol. And then I have one more question. Dr. Neeraj Badjatia: Sure, it’s a good point. The two studies done with volunteers and in, I think, the Paki setting demonstrated no significant benefit in terms of reducing the shivering threshold, but these were awake patients and otherwise not neurologically injured patients. They demonstrated a patient satisfaction in terms of the subjective feeling of cooling. So absolutely, you’re right; the two slides, the two studies that I put up at least don’t strongly argue in favor of that. In terms of clinical data, there isn’t a dose-finding clinical study that I’m aware of. But in terms of physiologic response, I think it makes sense. I think it is something that would be great to have in clinical studies and clinical trials, clinical dose finding. But I think the cutaneous vasodilatation that we do see, for which we have unpublished data where we actually measured skin temperature with advancing doses of MAG, is kind of how we came up with the 3–4 mg/dl. We certainly would be more effective if we went higher, but then you start to get some hemodynamic effect that interferes, and we also were a little leery of our patients, whose concomitant renal insufficiency may tip them over in terms of their level. Question: Great. Thanks. The second question is, the accelerometer data are fascinating. You alluded to using it in the machines that are driving the cooling. But since the machine can only change temperature, not sedation or antishivering measures, exactly how would that work, putting that input into the machine?
Cardiology, Lund University, Lund, Sweden. Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania. Internal Medicine, Abbott Northwestern Hospital, Minneapolis, Minnesota. Neurology, University of Maryland, Baltimore, Maryland.
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Dr. Neeraj Badjatia: Well, I think that is all still being thought out in terms of how we can work it. Correct, it wouldn’t deliver, and we’re not going to have this megadevice that is going to deliver drugs and all this other stuff. But maybe it is going to be tied into something else that is going to change the skin temperature. You know, maybe it is tied into another device that is working on skin temperature or something else that is helping us in terms of management. Right now the engineering is really driven to temperature itself. It is not driven to heat exchange per se. It is not driven to metabolic expenditure. I think that is a more sensitive way to control temperature. I’m not an engineer, so my naı¨ve nonengineering mind would think that we could target metabolic rates rather than just core temperature by itself, which is a crude end result of metabolic rates. That may lead to more sophisticated engineering design of how these devices work. Comment: Two quick points. You mention the idea of counterwarming. You’ll hear more about what we are doing in a community hospital tomorrow; we found that it was a very inexpensive way to at least do basic counterwarming with gloves and booties. Then at times warm on the face as you were mentioning, because we are using topical cooling with a head device. The other thing is in neurocritical care, again at the community hospital level, with traumatic brain injury we like LiCox monitoring. We have been using head wrap, and we do see temperature differentials or at least temperature controls. So I don’t know whether that’s a pro or a con to what you were saying about the effect of surface cooling and brain temperature. Dr. Neeraj Badjatia: Yes, when we actually first started using counterwarming, we actually did the same. We used gloves and booties and all of that. That seemed to work fairly well, but the devices we had somehow didn’t meet the muster for biomedical engineering at our institution, and we were told to stop using them, so that’s why we went to the Bair Hugger. But I think you probably don’t need full-body Bair Hugger. It’s not that complicated. It works, but if you could get away with just hands, feet, and neck or face warming, that’s probably going to be sufficient. Dr. Kelley Lockhart: I can comment on this too. We will wrap people in blankets so their head is wrapped, and they are completely wrapped up. It took us awhile to figure that out because for a period of time we would have our patients very exposed doing normothermia, and they were shivering. Once we figured out how to wrap them all up with the blankets and the gloves like you were talking about, as well as put the Bair Hugger on, they are quite awake and don’t need much sedation at all since they are not shivering that much. So I agree that you can do it, but as long as you are covering them, I think you have good shivering management. Dr. Kees Polderman: Can I comment too? Partly, it’s a differential between the core temperature and the skin temperature because of studies by Dr. Sessler’s group in the 1990s, where very mild hypothermia was induced and skin counterwarming didn’t seem to work very well. But if there is a bigger gradient, it does seem to work. Yeah, you can use different methods, and we tend to use both mixed up: we reproduce surface cooling; we will do hands and feet and face warming. We should actually do a study to compare the two
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methods, but the impression that we have in our awake patient studies is that both methods seem to work. Comment: In our country, we have some experience with patients awake during therapeutic hypothermia. I think that it is a very important issue. You should try to consider that if we can produce therapeutic hypothermia in the awake patient, it could reduce the number of days on ventilation and the patient can then eat on his or her own. We manage patients, with stroke and spinal cord injury, trying to conduct therapeutic hypothermia in awake patients. We have very nice outcomes regarding the comfort of the patient and the family. Question: I have two questions. The first is for Dr. Badjatia. In targeted temperature management (TTM), if you have to reach a goal temperature in a certain amount of time using your stepwise antishivering protocols, what time periods do you give between interventions to allow it to work? Dr. Neeraj Badjatia: So, as we are ordering the device, step 0 goes into place. We start the acetaminophen. We get the Bair Hugger ready. We start the magnesium, and the buspirone is administered. So we don’t wait for the device to turn on to do those things. The one thing we do not do is turn on the Bair Hugger until the device is on. Although we record hourly as we’re inducing, usually somebody is at the bedside who is able to administer drugs—nursing staff as well as nurse practitioners or physicians. We will, during the induction period, typically not wait very long if we are having difficulty; we will start dex rather quickly. I’ll give meperidine if I need to every 30 minutes to get them to stop shivering. But I think the induction period itself and the rewarming period are probably the two most dangerous periods in terms of effect on the patient, but also in terms of the shivering problems. So during those time periods, we are much more active than just every hour response. If we see shivering during maintenance and they don’t respond within 15–20 minutes given the pharmacokinetics of the drug that we happen to be using, then we’ll escalate. So we don’t necessarily wait an hour or two or three. We’ll try to get on top of it as soon as possible. Question: Thank you, and then my next question is for Dr. Lockhart. You state that fever is harmful to the brain yet it is the body’s natural response to fight off infection. With normal temperature therapy, do you find any longer bouts of infection in these patients? Dr. Kelley Lockhart: The answer is no. The infections are treated exactly the same way that they would be treated in standard situations. So the course of antibiotics for a urinary tract infection is a three-day course, and the patient responds appropriately. Pneumonia is treated in a seven-day course often. There’s no extended treatment because of normothermia, and I don’t see that the patients are having prolonged infections or prolonged difficulty clearing infection. In fact, when you are doing normothermia in a neuro-population, once you get rid of that fever, you really find that you don’t have a lot of infections in your patients. I think when they’re febrile probably just due to their neural injury you’re diagnosing infections that probably aren’t there. So you’re pulling out a culture with a Staphylococcus aureus contamination you’re treating despite no infiltrate on x-ray. You’re spending
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a lot of money looking for things and treating things that probably aren’t there. So when you are doing normothermia, the patients act the same way when they get an infection, but you are not diagnosing as many infections, and I think you are probably treating more appropriately than you would be if you just let them be febrile.
Dr. Kees Polderman: A brief comment on the IV acetaminophen: this has been available in Europe since I was a resident. It works the same way as orally, so it’s appropriate for patients who don’t have oral access, and it works slightly faster, but you can’t expect it to work better. So I don’t know why one would expect this to be a solution.
Comment and Question: I think that if you are looking at acetaminophen, the bioavailability orally is 100%. So it’s really an issue of dose. When you give the IV dose, you’re giving a gram, and unless you’ve maxed out the oral, you’re not going to see the same effects. Our institution spent a million dollars on IV acetaminophen last year. But the other question is whether any of you have looked at the synergy between acetaminophen and ibuprofen given together, because we are finding at least anecdotally that it seems to have not an additive but a synergistic effect in these refractory febrile patients that, even with our devices, are still breaking through. Do you have any general data or any specific temperature data from looking at the combination?
Dr. Neeraj Badjatia: My thought was to use it as continuous infusion actually. Unfortunately, the company did not agree with that concept, so we went to ibuprofen instead.
Dr. Neeraj Badjatia: Dr. Mike Dirringer’s group published on this recently in a small pilot trial, where they found that the combination led to a reduction in temperature. Whether it is clinically significant or not I think it was less than a degree centigrade difference. What we’re actually doing is going slightly different in how we’re approaching it. I agree with everyone that it was said that IV acetaminophen was a great idea. We all thought the same; we are going to use this, and we are not going to have to use as many devices, and so on, but it just hasn’t worked out that way. On the contrary, in our pilot trial we are actually doing continuous infusion of ibuprofen after subarachnoid hemorrhage or intracerebral hemorrhage. In those patients, and these are open-label randomized trials versus standard of care for fever, we’re finding a significant reduction in temperature, with significantly less shivering if they end up on a device. Actually, they are ending up on a device a little bit less often than our standard of care. We thought about combining that with acetaminophen, but in order to make the study clean, we kind of kept it that way. Anecdotally, I have started using PO ibuprofen and PO acetaminophen together. I would agree that it does have more bang for your buck, if you will, than just one by itself. Comment: Thank you. I think we’ve looked at the ibuprofen issue in a series of patients, and the two that you have to be extremely careful with are the ones that are using concurrent vancomycin and going for contrast imaging. In the vasospasm patients who are then going for computed tomography angiography (CTA), if you have high doses of that and they happen to be on vancomycin and get contrast, you’ll almost always find an acute kidney injury with those people. Dr. Neeraj Badjatia: So we’re tracking acute kidney injury (AKI) as one of our end points. We have not had any AKIs in our patients; these are all high-grade subarachnoid hemorrhage patients, and we’ll do multiple CTAs and angios during their two-week course. None have met rifle criteria for injury yet. I’m waiting for it to happen, but not yet. So it is absolutely right; it’s something that we are going to have watch. I think what happens also with these folks; they get a lot of fluids that may or may not help mitigate some of their problems.
Dr. Kelley Lockhart: My point in putting up the slide of IV acetaminophen is that if anybody was thinking that it was going to be easier than using one of these devices, I wanted to share our experience over the last couple of years. Question: I have a few questions to Dr. Polderman first. You showed in your slide that you are not delaying therapy with opening the vessels by cooling first. But if you want to have good results, you should have cooled them to reach your target temperature before you opened the vessel. Are you going so far that you delayed your therapy because hypothermia would be best before opening your vessel and getting reflow preventing ischemic reperfusion? Dr. Kees Polderman: It’s an excellent question. But first, I agree; I think that’s true, but we don’t know that. We don’t know if you have to cool before reperfusion. We know from studies in myocardial infarction that this appears to be so. We don’t know this for the brain. But we try to do this. Our cooling actually takes place before opening the vessel, but we don’t delay the opening of the vessel. In stroke, it’s a little bit easier because it is not like with AMI where you open the coronary all at once, but in stroke you usually take the clots out bit by bit and this takes time. Our cooling time to get to below 34 is actually 23 minutes, so that is pretty fast. We were able to have this temperature in most of our patients before the vessel is opened, and even if the beginning of the opening of the vessel is already taking place, there are still some vessels that are known to be opened in the subsequent hour or so that it takes to do this procedure. I think probably it is better to cool before reperfusion, but we know that the recent TTM trial casts some doubt on that. Yet, cooling after the event and ischemic injury still seems to work if you do it long enough, so it’s an open question whether or not we have to do it before reperfusion or not. Question: Question for Dr. Lockhart concerning infection. Do you consider selective decontamination in your hospital? Dr. Kelley Lockhart: No, we don’t do that. Question: I’ve got another question for Dr. Badjatia. When we talk about shivering, everybody looks at the temperature. But I’m more concerned about the CO2 production, because when CO2 production goes up it influences the bloodstream in your brain. It increases. So probably brain edema and other things could happen too. Are you aware of any studies looking at CO2 and shivering in the outcome? Dr. Neeraj Badjatia: Not outcome. But I think clinically we completely agree with that. In fact, that is usually one of the
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first signs I see. I’ve stopped really looking at the shivering score. I go in and look at intubated patients and look at the ventilator, because you suddenly start to see huge tidal lines, a liter. That’s when you know that something is not going well. And so, as part of our routine monitoring now, we do end tidal CO2 on every patient, but certainly even on the TTM patients we are using noninvasive CO2 monitoring that I think is a big issue in the ones who aren’t intubated. I don’t know of any clinical studies looking at outcome, but clinically it has made it into our data collection for all of our TTM patients. Question: I’ve got one last question. I don’t know if I ask it to Dr. Polderman or Dr. Badjatia. But if you look at bears, bears are not shivering when they are cooling down to hibernate. Do we know why they don’t shiver? Dr. Kees Polderman: There is a whole field of hibernation and how animals tolerate very deep hypothermia, and there is a long answer to your question but the short answer is we don’t know. Question: I also have two questions, and I apologize that the first one is very basic, but why does the body decrease its shivering response at lower temperatures? Dr. Kees Polderman: We don’t know. It’s actually very nonphysiologic, because if it happens in nature, you die from hypothermia. If you stop shivering you become calm and lethargic, and so it’s an inappropriate response. But it happens, and we can use it therapeutically, but there is no good reason for it as far as we know. Question: Maybe this will be addressed tomorrow, but I’m a cardiologist and as we’re moving from cutaneous cooling to central cooling, you have less vasoconstriction. I assume in somebody with low cardiac output that it would improve hemodynamics. I know it’s depressed during that. I don’t know if there is any metabolic marker, in particular in those patients with low cardiac output, whether decreasing that after load is helpful? Dr. Kelley Lockhart: So, the surface cooling versus the intravascular cooling, there’s not a big difference on change in hemodynamics. So we have a big cardiac arrest program in Abbott Northwestern, and we switched from Artic Sun surface cooling to the intravascular cooling, and there has not been a change in hemodynamics or cardiac output profile in those patients. We were able to safely do that. The only advantage was that we got a triple lumen at the same time that we put on the intravascular catheter. But we can certainly talk more. We have our program coordinator for the study here too. But the vasoconstriction of that surface constriction is not going to change our hemodynamics significantly. Dr. Kees Polderman: The hypothermia itself causes invasive constriction. It’s independent of the method that you use. Nicholas, do you want to comment on this in the TTM trial? I’m assuming that you guys looked or maybe you are still looking at this. Are there differences between surface cooling and IV cooling?
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Response: Yes, we had 24% IV cooling and the rest surface cooling, and we are planning to look at the groups separately and publish that. But I don’t have any results yet. Question: Thanks. I’m a cardiologist in the UK, and I just want to turn the interest to reperfusion and cooling and STEMI. Do you think that the shivering is so important to be really well controlled that it could have an adverse effect on outcomes? So, from a cardiologist’s perspective, we just want to cool the patient to less than 35 and open the entry. I wonder if when you’ve taken shivering to the next level for us, do you think it could be so important that we need to really up our game with shivering, understanding, and management of that per se rather than just being a bit of a pain for the patient? Dr. Kelley Lockhart: All of us are going to say yes; you need to up your game for shivering management because the patients will have increased infection and aspiration if shivering is uncontrolled. And if you’re going down to 35, that is the time period when they’re really shivering. Dr. Kees Polderman: And they’ll become tachycardic, and that would be bad. Dr. Erlinge is going to present his study tomorrow in the COOL-MI and can comment briefly on that. I think if you get to the point where the patient becomes tachycardic, then you might very well harm the patient. So, it’s more than just discomfort. It really needs to be managed, at least to the point where it doesn’t cause severe symptoms like tachycardia. Dr. David Erlinge: Our experience, like in the videos and as Kees Polderman showed, is that the patients tolerate cooling very well when they are awake. As soon as they start shivering or the temperature rises of course, that’s when the problems occur. So, just a quick dose of meperidine brings them back from shivering in just a few minutes. I think all those doses of meperidine are very efficient. That was actually my question as well. We use meperidine a lot in Sweden, and we think it’s very effective. To my knowledge there are quite good data on that. It’s one of the most effective drugs to lower the temperature threshold. Dr. Neeraj Badjatia: Absolutely, it’s an opiate that has central-alpha effects. It is unique in its properties. There is a lot of misbelief, I’d say, about demerol and seizure risk, and it doesn’t occur. I mean just to put it out there, we don’t ever see seizures, and in fact the reports of seizures with the use of demerol really come from case reports. In those case reports, those are patients who, from what I understand, are really hard to find. I know Dr. Lyden has looked at this in great detail for his study. But really, it just does not occur outside of renal insufficiency, and even in the renal insufficient patient, you have meperidine, which is a metabolite that increases and perhaps just changes seizure threshold, but clinically this has not been reported. So I know it’s one of those warnings included for meperidine. When we first started doing this, we were putting people on demerol drips. We have backed away from that for a set of sedation issues, but we never saw seizures in brain-injured patients. Dr. Kees Polderman: I totally agree. I infused this both in my myocardial infarction studies and in the stroke studies,
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and it’s not an issue. Just put both doses, as they’ve described, in the patient. If you see shivering, it is also important basically to nip it in the bud. If you get into full-blown shivering mode, it is much more difficult to control than when you kind of control it earlier. Question: It’s a question about central and peripheral hyper pyrexia. I’m from Colorado, and it comes as a little surprise to me. I have a lot of patients with substance dependency and substance use disorder-related problems. Particularly a large number of psychiatric patients with the form first of neuroleptic malignant syndrome, and a large number of patients that have hypothermia. We’ve noticed a rather unique difference in normothermic targeting in those patients, and this is all in peripheral hyper pyrexia as opposed to postrewarming hypothermia if you want. I would be interested in what your guidance is, and whether defending the higher temperatures is justified in these patients? All of those patients shiver like crazy as soon as you start cooling them down. I wondered what your thoughts were? Dr. Kelley Lockhart: Yeah, I can talk a little bit about our experience with those types of patients. One thing that I’ve noticed is that they are often young thin males with a lot of muscle mass. Those are the ones that are already shivering that are difficult to control to begin with. So, it’s sometimes the patient population instead of the peripheral versus central mechanisms. They are more difficult to control and sometimes require sedating medications to bring them down. In the rare case that we are going to paralyze them, if we really feel that the fever is harmful, and you’ve got temperatures of 105– 106 that you are trying to cool. We’ve been in that situation too, and then you’re also using medications to try to reverse that. Those are difficult-to-manage patients, but I think it’s more of the patient population of young, thin, healthy males; the ones who don’t shiver tend to be the ones with a lot of adipose tissue and elderly patients. Those ones are really easy to cool. A female with a little central round ample figure who is about 70 years old is your dream patient to put in a catheter and induce normothermia. But the young male who runs a marathon is going to be difficult to control. Dr. Neeraj Badjatia: The one thing I’d say, regarding the N-methyl-D-asparate-type drugs that are out there and fever with those patients, don’t forget that the mechanism is slightly different. You’ve got to target the basal ganglia receptors as well. So we use a lot of endoral and bromocryptine as part of our first line. That actually helps in terms of the storming sympathetic surge that you see in those patients. Comment: We’ve had a fair number of these patients and also malignant hyperthermia from these patients on adrenergic surge drugs that the police take. Strangely enough, the drug that has been most beneficial for us in controlling this is ketamine. We are being very aggressive even in the
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prehospital with the use of ketamine because of our transport times. This has been, I think, an underappreciated drug for this type of patient. Dr. Neeraj Badjatia: I completely agree with you, and our rate-limiting step is getting our hospital, and quite frankly some of our anesthesiologists, to let go of their grip on ketamine. But we completely agree with that. We’ve had some great responses with ketamine use, but we are limited by our institutional restrictions on how we can use it. Key References from Panel Participants
Andrews PJ, Sinclair HL, Battison CG, Polderman KH, Citerio G, Mascia L, Harris BA, Murray GD, Stocchetti N, Menon DK, Shakur H, De Backer D; Eurotherm3235Trial Collaborators. European society of intensive care medicine study of therapeutic hypothermia (32–35C) for intracranial pressure reduction after traumatic brain injury (the Eurotherm3235Trial). Trials 2011;12:8. Badjatia N. Fever control in the NICU: is there still a simpler and cheaper solution? Neurocrit Care 2011;15:373–374. Badjatia N. Hypothermia in neurocritical care. Neurosurg Clin N Am 2013;24:457–467. Choi HA, Badjatia N, Mayer SA. Hypothermia for acute brain injury—mechanisms and practical aspects. Nat Rev Neurol 2012;8:214–222. de Waard MC, Biermann H, Brinckman SL, Appelman YE, Driessen RH, Polderman KH, Girbes AR, Beishuizen A. Automated peritoneal lavage: an extremely rapid and safe way to induce hypothermia in post-resuscitation patients. Crit Care 2013;17:R31. Lord AS, Karinja S, Lantigua H, Carpenter A, Schmidt JM, Claassen J, Agarwal S, Connolly ES, Mayer SA, Badjatia N. Therapeutic temperature modulation for fever after intracerebral hemorrhage. Neurocrit Care 2014 [Epub ahead of print]. Nielsen N, Wetterslev J, Cronberg T, Erlinge D, Gasche Y, Hassager C, Horn J, Hovdenes J, Kjaergaard J, Kuiper M, ˚ neman A, AlPellis T, Stammet P, Wanscher M, Wise MP, A Subaie N, Boesgaard S, Bro-Jeppesen J, Brunetti I, Bugge JF, Hingston CD, Juffermans NP, Koopmans M, Køber L, Langørgen J, Lilja G, Møller JE, Rundgren M, Rylander C, Smid O, Werer C, Winkel P, Friberg H; TTM Trial Investigators. Targeted temperature management at 33C versus 36C after cardiac arrest. N Engl J Med 2013;369:2197–2206. Polderman KH. Of ions and temperature: the complicated interplay of temperature, fluids, and electrolytes on myocardial function. Crit Care 2013;17:1018. Polderman KH, Andrews PJ. Hypothermia in patients with brain injury: the way forward? Lancet Neurol 2011;10:404– 405; author reply 406–407. Rittenberger JC, Polderman KH, Smith WS, Weingart SD. Emergency neurological life support: resuscitation following cardiac arrest. Neurocrit Care 2012;17 Suppl 1:S21–S28. van Zanten AR, Polderman KH. Blowing hot and cold? Skin counter warming to prevent shivering during therapeutic cooling. Crit Care Med 2009;37:2106–2108.
Expert Panel Discussions
Temperature Management in Neurological and Neurosurgical Intensive Care Units Moderator: David Erlinge, MD, PhD1 Participants: Kees Polderman, MD, PhD,2 Kelley Lockhart, MD,3 and Neeraj Badjatia, MD 4
The use of temperature management in neurological and neurosurgical intensive care units (ICU) has gained acceptance and resulted in better outcomes in some patient populations. In various studies of out-of-hospital cardiac arrest as well as traumatic brain injury, directed temperature management protocols in the ICU have led to reductions in periods of reactive hyperthermia that occur in many patients with severe injuries. In addition, lowering the temperature to various levels of hypothermia also appears to reduce secondary injury mechanisms, intracranial pressure levels, and edema formation. Nevertheless, controversies exist in what patient population we should cool and what level of cooling is most appropriate in neurological settings. A series of stateof-the-art lectures presented at the 2014 Therapeutic Hypothermia and Temperature Management meeting in Miami brought together experts in the field of therapeutic hypothermia and temperature management strategies to discuss this important topic. Dr. Kees Polderman, Department of Critical Care, University of Pittsburgh School of Medicine, Pittsburgh, PA, provided new information regarding the reasons to cool patients and new strategies for cooling awake patients, which is an important clinical question. In the awake state, patients shiver and this can produce barriers to reducing temperature effectively and making the patient comfortable. Dr. Kelley Lockhart, Department of Internal Medicine, Abbott Northwestern Hospital, Minneapolis, MN, emphasized the potentially detrimental effects of fever in various patient populations, including subarachnoid hemorrhage. In these patients specifically, 70% develop fever during the first 10 days. Although it is difficult to determine causes underlying elevations in temperature, hyperthermia continues to be a risk factor that may be controlled by targeted temperature management. Dr. Neeraj Badjatia, Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, described novel approaches to monitor degrees of shivering in patient populations. Continuing studies are directed toward understanding the clinical relevance of shivering as well as antishivering strategies that may allow cooling to be introduced in the awake subject. 1
Department Department Department 4 Department 2 3
of of of of
It is clear that as therapeutic hypothermia and temperature management strategies are increasingly used by many caregivers, these types of questions are becoming more and more important to define and provide suitable strategies for better outcomes. Question: Two questions. First, you showed some slides containing data on magnesium that was not supportive of your thesis, and I wonder if you could speak a little bit more rigorously about the data that prove whether or not magnesium is part of the protocol. And then I have one more question. Dr. Neeraj Badjatia: Sure, it’s a good point. The two studies done with volunteers and in, I think, the Paki setting demonstrated no significant benefit in terms of reducing the shivering threshold, but these were awake patients and otherwise not neurologically injured patients. They demonstrated a patient satisfaction in terms of the subjective feeling of cooling. So absolutely, you’re right; the two slides, the two studies that I put up at least don’t strongly argue in favor of that. In terms of clinical data, there isn’t a dose-finding clinical study that I’m aware of. But in terms of physiologic response, I think it makes sense. I think it is something that would be great to have in clinical studies and clinical trials, clinical dose finding. But I think the cutaneous vasodilatation that we do see, for which we have unpublished data where we actually measured skin temperature with advancing doses of MAG, is kind of how we came up with the 3–4 mg/dl. We certainly would be more effective if we went higher, but then you start to get some hemodynamic effect that interferes, and we also were a little leery of our patients, whose concomitant renal insufficiency may tip them over in terms of their level. Question: Great. Thanks. The second question is, the accelerometer data are fascinating. You alluded to using it in the machines that are driving the cooling. But since the machine can only change temperature, not sedation or antishivering measures, exactly how would that work, putting that input into the machine?
Cardiology, Lund University, Lund, Sweden. Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania. Internal Medicine, Abbott Northwestern Hospital, Minneapolis, Minnesota. Neurology, University of Maryland, Baltimore, Maryland.
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Dr. Neeraj Badjatia: Well, I think that is all still being thought out in terms of how we can work it. Correct, it wouldn’t deliver, and we’re not going to have this megadevice that is going to deliver drugs and all this other stuff. But maybe it is going to be tied into something else that is going to change the skin temperature. You know, maybe it is tied into another device that is working on skin temperature or something else that is helping us in terms of management. Right now the engineering is really driven to temperature itself. It is not driven to heat exchange per se. It is not driven to metabolic expenditure. I think that is a more sensitive way to control temperature. I’m not an engineer, so my naı¨ve nonengineering mind would think that we could target metabolic rates rather than just core temperature by itself, which is a crude end result of metabolic rates. That may lead to more sophisticated engineering design of how these devices work. Comment: Two quick points. You mention the idea of counterwarming. You’ll hear more about what we are doing in a community hospital tomorrow; we found that it was a very inexpensive way to at least do basic counterwarming with gloves and booties. Then at times warm on the face as you were mentioning, because we are using topical cooling with a head device. The other thing is in neurocritical care, again at the community hospital level, with traumatic brain injury we like LiCox monitoring. We have been using head wrap, and we do see temperature differentials or at least temperature controls. So I don’t know whether that’s a pro or a con to what you were saying about the effect of surface cooling and brain temperature. Dr. Neeraj Badjatia: Yes, when we actually first started using counterwarming, we actually did the same. We used gloves and booties and all of that. That seemed to work fairly well, but the devices we had somehow didn’t meet the muster for biomedical engineering at our institution, and we were told to stop using them, so that’s why we went to the Bair Hugger. But I think you probably don’t need full-body Bair Hugger. It’s not that complicated. It works, but if you could get away with just hands, feet, and neck or face warming, that’s probably going to be sufficient. Dr. Kelley Lockhart: I can comment on this too. We will wrap people in blankets so their head is wrapped, and they are completely wrapped up. It took us awhile to figure that out because for a period of time we would have our patients very exposed doing normothermia, and they were shivering. Once we figured out how to wrap them all up with the blankets and the gloves like you were talking about, as well as put the Bair Hugger on, they are quite awake and don’t need much sedation at all since they are not shivering that much. So I agree that you can do it, but as long as you are covering them, I think you have good shivering management. Dr. Kees Polderman: Can I comment too? Partly, it’s a differential between the core temperature and the skin temperature because of studies by Dr. Sessler’s group in the 1990s, where very mild hypothermia was induced and skin counterwarming didn’t seem to work very well. But if there is a bigger gradient, it does seem to work. Yeah, you can use different methods, and we tend to use both mixed up: we reproduce surface cooling; we will do hands and feet and face warming. We should actually do a study to compare the two
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methods, but the impression that we have in our awake patient studies is that both methods seem to work. Comment: In our country, we have some experience with patients awake during therapeutic hypothermia. I think that it is a very important issue. You should try to consider that if we can produce therapeutic hypothermia in the awake patient, it could reduce the number of days on ventilation and the patient can then eat on his or her own. We manage patients, with stroke and spinal cord injury, trying to conduct therapeutic hypothermia in awake patients. We have very nice outcomes regarding the comfort of the patient and the family. Question: I have two questions. The first is for Dr. Badjatia. In targeted temperature management (TTM), if you have to reach a goal temperature in a certain amount of time using your stepwise antishivering protocols, what time periods do you give between interventions to allow it to work? Dr. Neeraj Badjatia: So, as we are ordering the device, step 0 goes into place. We start the acetaminophen. We get the Bair Hugger ready. We start the magnesium, and the buspirone is administered. So we don’t wait for the device to turn on to do those things. The one thing we do not do is turn on the Bair Hugger until the device is on. Although we record hourly as we’re inducing, usually somebody is at the bedside who is able to administer drugs—nursing staff as well as nurse practitioners or physicians. We will, during the induction period, typically not wait very long if we are having difficulty; we will start dex rather quickly. I’ll give meperidine if I need to every 30 minutes to get them to stop shivering. But I think the induction period itself and the rewarming period are probably the two most dangerous periods in terms of effect on the patient, but also in terms of the shivering problems. So during those time periods, we are much more active than just every hour response. If we see shivering during maintenance and they don’t respond within 15–20 minutes given the pharmacokinetics of the drug that we happen to be using, then we’ll escalate. So we don’t necessarily wait an hour or two or three. We’ll try to get on top of it as soon as possible. Question: Thank you, and then my next question is for Dr. Lockhart. You state that fever is harmful to the brain yet it is the body’s natural response to fight off infection. With normal temperature therapy, do you find any longer bouts of infection in these patients? Dr. Kelley Lockhart: The answer is no. The infections are treated exactly the same way that they would be treated in standard situations. So the course of antibiotics for a urinary tract infection is a three-day course, and the patient responds appropriately. Pneumonia is treated in a seven-day course often. There’s no extended treatment because of normothermia, and I don’t see that the patients are having prolonged infections or prolonged difficulty clearing infection. In fact, when you are doing normothermia in a neuro-population, once you get rid of that fever, you really find that you don’t have a lot of infections in your patients. I think when they’re febrile probably just due to their neural injury you’re diagnosing infections that probably aren’t there. So you’re pulling out a culture with a Staphylococcus aureus contamination you’re treating despite no infiltrate on x-ray. You’re spending
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a lot of money looking for things and treating things that probably aren’t there. So when you are doing normothermia, the patients act the same way when they get an infection, but you are not diagnosing as many infections, and I think you are probably treating more appropriately than you would be if you just let them be febrile.
Dr. Kees Polderman: A brief comment on the IV acetaminophen: this has been available in Europe since I was a resident. It works the same way as orally, so it’s appropriate for patients who don’t have oral access, and it works slightly faster, but you can’t expect it to work better. So I don’t know why one would expect this to be a solution.
Comment and Question: I think that if you are looking at acetaminophen, the bioavailability orally is 100%. So it’s really an issue of dose. When you give the IV dose, you’re giving a gram, and unless you’ve maxed out the oral, you’re not going to see the same effects. Our institution spent a million dollars on IV acetaminophen last year. But the other question is whether any of you have looked at the synergy between acetaminophen and ibuprofen given together, because we are finding at least anecdotally that it seems to have not an additive but a synergistic effect in these refractory febrile patients that, even with our devices, are still breaking through. Do you have any general data or any specific temperature data from looking at the combination?
Dr. Neeraj Badjatia: My thought was to use it as continuous infusion actually. Unfortunately, the company did not agree with that concept, so we went to ibuprofen instead.
Dr. Neeraj Badjatia: Dr. Mike Dirringer’s group published on this recently in a small pilot trial, where they found that the combination led to a reduction in temperature. Whether it is clinically significant or not I think it was less than a degree centigrade difference. What we’re actually doing is going slightly different in how we’re approaching it. I agree with everyone that it was said that IV acetaminophen was a great idea. We all thought the same; we are going to use this, and we are not going to have to use as many devices, and so on, but it just hasn’t worked out that way. On the contrary, in our pilot trial we are actually doing continuous infusion of ibuprofen after subarachnoid hemorrhage or intracerebral hemorrhage. In those patients, and these are open-label randomized trials versus standard of care for fever, we’re finding a significant reduction in temperature, with significantly less shivering if they end up on a device. Actually, they are ending up on a device a little bit less often than our standard of care. We thought about combining that with acetaminophen, but in order to make the study clean, we kind of kept it that way. Anecdotally, I have started using PO ibuprofen and PO acetaminophen together. I would agree that it does have more bang for your buck, if you will, than just one by itself. Comment: Thank you. I think we’ve looked at the ibuprofen issue in a series of patients, and the two that you have to be extremely careful with are the ones that are using concurrent vancomycin and going for contrast imaging. In the vasospasm patients who are then going for computed tomography angiography (CTA), if you have high doses of that and they happen to be on vancomycin and get contrast, you’ll almost always find an acute kidney injury with those people. Dr. Neeraj Badjatia: So we’re tracking acute kidney injury (AKI) as one of our end points. We have not had any AKIs in our patients; these are all high-grade subarachnoid hemorrhage patients, and we’ll do multiple CTAs and angios during their two-week course. None have met rifle criteria for injury yet. I’m waiting for it to happen, but not yet. So it is absolutely right; it’s something that we are going to have watch. I think what happens also with these folks; they get a lot of fluids that may or may not help mitigate some of their problems.
Dr. Kelley Lockhart: My point in putting up the slide of IV acetaminophen is that if anybody was thinking that it was going to be easier than using one of these devices, I wanted to share our experience over the last couple of years. Question: I have a few questions to Dr. Polderman first. You showed in your slide that you are not delaying therapy with opening the vessels by cooling first. But if you want to have good results, you should have cooled them to reach your target temperature before you opened the vessel. Are you going so far that you delayed your therapy because hypothermia would be best before opening your vessel and getting reflow preventing ischemic reperfusion? Dr. Kees Polderman: It’s an excellent question. But first, I agree; I think that’s true, but we don’t know that. We don’t know if you have to cool before reperfusion. We know from studies in myocardial infarction that this appears to be so. We don’t know this for the brain. But we try to do this. Our cooling actually takes place before opening the vessel, but we don’t delay the opening of the vessel. In stroke, it’s a little bit easier because it is not like with AMI where you open the coronary all at once, but in stroke you usually take the clots out bit by bit and this takes time. Our cooling time to get to below 34 is actually 23 minutes, so that is pretty fast. We were able to have this temperature in most of our patients before the vessel is opened, and even if the beginning of the opening of the vessel is already taking place, there are still some vessels that are known to be opened in the subsequent hour or so that it takes to do this procedure. I think probably it is better to cool before reperfusion, but we know that the recent TTM trial casts some doubt on that. Yet, cooling after the event and ischemic injury still seems to work if you do it long enough, so it’s an open question whether or not we have to do it before reperfusion or not. Question: Question for Dr. Lockhart concerning infection. Do you consider selective decontamination in your hospital? Dr. Kelley Lockhart: No, we don’t do that. Question: I’ve got another question for Dr. Badjatia. When we talk about shivering, everybody looks at the temperature. But I’m more concerned about the CO2 production, because when CO2 production goes up it influences the bloodstream in your brain. It increases. So probably brain edema and other things could happen too. Are you aware of any studies looking at CO2 and shivering in the outcome? Dr. Neeraj Badjatia: Not outcome. But I think clinically we completely agree with that. In fact, that is usually one of the
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first signs I see. I’ve stopped really looking at the shivering score. I go in and look at intubated patients and look at the ventilator, because you suddenly start to see huge tidal lines, a liter. That’s when you know that something is not going well. And so, as part of our routine monitoring now, we do end tidal CO2 on every patient, but certainly even on the TTM patients we are using noninvasive CO2 monitoring that I think is a big issue in the ones who aren’t intubated. I don’t know of any clinical studies looking at outcome, but clinically it has made it into our data collection for all of our TTM patients. Question: I’ve got one last question. I don’t know if I ask it to Dr. Polderman or Dr. Badjatia. But if you look at bears, bears are not shivering when they are cooling down to hibernate. Do we know why they don’t shiver? Dr. Kees Polderman: There is a whole field of hibernation and how animals tolerate very deep hypothermia, and there is a long answer to your question but the short answer is we don’t know. Question: I also have two questions, and I apologize that the first one is very basic, but why does the body decrease its shivering response at lower temperatures? Dr. Kees Polderman: We don’t know. It’s actually very nonphysiologic, because if it happens in nature, you die from hypothermia. If you stop shivering you become calm and lethargic, and so it’s an inappropriate response. But it happens, and we can use it therapeutically, but there is no good reason for it as far as we know. Question: Maybe this will be addressed tomorrow, but I’m a cardiologist and as we’re moving from cutaneous cooling to central cooling, you have less vasoconstriction. I assume in somebody with low cardiac output that it would improve hemodynamics. I know it’s depressed during that. I don’t know if there is any metabolic marker, in particular in those patients with low cardiac output, whether decreasing that after load is helpful? Dr. Kelley Lockhart: So, the surface cooling versus the intravascular cooling, there’s not a big difference on change in hemodynamics. So we have a big cardiac arrest program in Abbott Northwestern, and we switched from Artic Sun surface cooling to the intravascular cooling, and there has not been a change in hemodynamics or cardiac output profile in those patients. We were able to safely do that. The only advantage was that we got a triple lumen at the same time that we put on the intravascular catheter. But we can certainly talk more. We have our program coordinator for the study here too. But the vasoconstriction of that surface constriction is not going to change our hemodynamics significantly. Dr. Kees Polderman: The hypothermia itself causes invasive constriction. It’s independent of the method that you use. Nicholas, do you want to comment on this in the TTM trial? I’m assuming that you guys looked or maybe you are still looking at this. Are there differences between surface cooling and IV cooling?
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Response: Yes, we had 24% IV cooling and the rest surface cooling, and we are planning to look at the groups separately and publish that. But I don’t have any results yet. Question: Thanks. I’m a cardiologist in the UK, and I just want to turn the interest to reperfusion and cooling and STEMI. Do you think that the shivering is so important to be really well controlled that it could have an adverse effect on outcomes? So, from a cardiologist’s perspective, we just want to cool the patient to less than 35 and open the entry. I wonder if when you’ve taken shivering to the next level for us, do you think it could be so important that we need to really up our game with shivering, understanding, and management of that per se rather than just being a bit of a pain for the patient? Dr. Kelley Lockhart: All of us are going to say yes; you need to up your game for shivering management because the patients will have increased infection and aspiration if shivering is uncontrolled. And if you’re going down to 35, that is the time period when they’re really shivering. Dr. Kees Polderman: And they’ll become tachycardic, and that would be bad. Dr. Erlinge is going to present his study tomorrow in the COOL-MI and can comment briefly on that. I think if you get to the point where the patient becomes tachycardic, then you might very well harm the patient. So, it’s more than just discomfort. It really needs to be managed, at least to the point where it doesn’t cause severe symptoms like tachycardia. Dr. David Erlinge: Our experience, like in the videos and as Kees Polderman showed, is that the patients tolerate cooling very well when they are awake. As soon as they start shivering or the temperature rises of course, that’s when the problems occur. So, just a quick dose of meperidine brings them back from shivering in just a few minutes. I think all those doses of meperidine are very efficient. That was actually my question as well. We use meperidine a lot in Sweden, and we think it’s very effective. To my knowledge there are quite good data on that. It’s one of the most effective drugs to lower the temperature threshold. Dr. Neeraj Badjatia: Absolutely, it’s an opiate that has central-alpha effects. It is unique in its properties. There is a lot of misbelief, I’d say, about demerol and seizure risk, and it doesn’t occur. I mean just to put it out there, we don’t ever see seizures, and in fact the reports of seizures with the use of demerol really come from case reports. In those case reports, those are patients who, from what I understand, are really hard to find. I know Dr. Lyden has looked at this in great detail for his study. But really, it just does not occur outside of renal insufficiency, and even in the renal insufficient patient, you have meperidine, which is a metabolite that increases and perhaps just changes seizure threshold, but clinically this has not been reported. So I know it’s one of those warnings included for meperidine. When we first started doing this, we were putting people on demerol drips. We have backed away from that for a set of sedation issues, but we never saw seizures in brain-injured patients. Dr. Kees Polderman: I totally agree. I infused this both in my myocardial infarction studies and in the stroke studies,
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and it’s not an issue. Just put both doses, as they’ve described, in the patient. If you see shivering, it is also important basically to nip it in the bud. If you get into full-blown shivering mode, it is much more difficult to control than when you kind of control it earlier. Question: It’s a question about central and peripheral hyper pyrexia. I’m from Colorado, and it comes as a little surprise to me. I have a lot of patients with substance dependency and substance use disorder-related problems. Particularly a large number of psychiatric patients with the form first of neuroleptic malignant syndrome, and a large number of patients that have hypothermia. We’ve noticed a rather unique difference in normothermic targeting in those patients, and this is all in peripheral hyper pyrexia as opposed to postrewarming hypothermia if you want. I would be interested in what your guidance is, and whether defending the higher temperatures is justified in these patients? All of those patients shiver like crazy as soon as you start cooling them down. I wondered what your thoughts were? Dr. Kelley Lockhart: Yeah, I can talk a little bit about our experience with those types of patients. One thing that I’ve noticed is that they are often young thin males with a lot of muscle mass. Those are the ones that are already shivering that are difficult to control to begin with. So, it’s sometimes the patient population instead of the peripheral versus central mechanisms. They are more difficult to control and sometimes require sedating medications to bring them down. In the rare case that we are going to paralyze them, if we really feel that the fever is harmful, and you’ve got temperatures of 105– 106 that you are trying to cool. We’ve been in that situation too, and then you’re also using medications to try to reverse that. Those are difficult-to-manage patients, but I think it’s more of the patient population of young, thin, healthy males; the ones who don’t shiver tend to be the ones with a lot of adipose tissue and elderly patients. Those ones are really easy to cool. A female with a little central round ample figure who is about 70 years old is your dream patient to put in a catheter and induce normothermia. But the young male who runs a marathon is going to be difficult to control. Dr. Neeraj Badjatia: The one thing I’d say, regarding the N-methyl-D-asparate-type drugs that are out there and fever with those patients, don’t forget that the mechanism is slightly different. You’ve got to target the basal ganglia receptors as well. So we use a lot of endoral and bromocryptine as part of our first line. That actually helps in terms of the storming sympathetic surge that you see in those patients. Comment: We’ve had a fair number of these patients and also malignant hyperthermia from these patients on adrenergic surge drugs that the police take. Strangely enough, the drug that has been most beneficial for us in controlling this is ketamine. We are being very aggressive even in the
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prehospital with the use of ketamine because of our transport times. This has been, I think, an underappreciated drug for this type of patient. Dr. Neeraj Badjatia: I completely agree with you, and our rate-limiting step is getting our hospital, and quite frankly some of our anesthesiologists, to let go of their grip on ketamine. But we completely agree with that. We’ve had some great responses with ketamine use, but we are limited by our institutional restrictions on how we can use it. Key References from Panel Participants
Andrews PJ, Sinclair HL, Battison CG, Polderman KH, Citerio G, Mascia L, Harris BA, Murray GD, Stocchetti N, Menon DK, Shakur H, De Backer D; Eurotherm3235Trial Collaborators. European society of intensive care medicine study of therapeutic hypothermia (32–35C) for intracranial pressure reduction after traumatic brain injury (the Eurotherm3235Trial). Trials 2011;12:8. Badjatia N. Fever control in the NICU: is there still a simpler and cheaper solution? Neurocrit Care 2011;15:373–374. Badjatia N. Hypothermia in neurocritical care. Neurosurg Clin N Am 2013;24:457–467. Choi HA, Badjatia N, Mayer SA. Hypothermia for acute brain injury—mechanisms and practical aspects. Nat Rev Neurol 2012;8:214–222. de Waard MC, Biermann H, Brinckman SL, Appelman YE, Driessen RH, Polderman KH, Girbes AR, Beishuizen A. Automated peritoneal lavage: an extremely rapid and safe way to induce hypothermia in post-resuscitation patients. Crit Care 2013;17:R31. Lord AS, Karinja S, Lantigua H, Carpenter A, Schmidt JM, Claassen J, Agarwal S, Connolly ES, Mayer SA, Badjatia N. Therapeutic temperature modulation for fever after intracerebral hemorrhage. Neurocrit Care 2014 [Epub ahead of print]. Nielsen N, Wetterslev J, Cronberg T, Erlinge D, Gasche Y, Hassager C, Horn J, Hovdenes J, Kjaergaard J, Kuiper M, ˚ neman A, AlPellis T, Stammet P, Wanscher M, Wise MP, A Subaie N, Boesgaard S, Bro-Jeppesen J, Brunetti I, Bugge JF, Hingston CD, Juffermans NP, Koopmans M, Køber L, Langørgen J, Lilja G, Møller JE, Rundgren M, Rylander C, Smid O, Werer C, Winkel P, Friberg H; TTM Trial Investigators. Targeted temperature management at 33C versus 36C after cardiac arrest. N Engl J Med 2013;369:2197–2206. Polderman KH. Of ions and temperature: the complicated interplay of temperature, fluids, and electrolytes on myocardial function. Crit Care 2013;17:1018. Polderman KH, Andrews PJ. Hypothermia in patients with brain injury: the way forward? Lancet Neurol 2011;10:404– 405; author reply 406–407. Rittenberger JC, Polderman KH, Smith WS, Weingart SD. Emergency neurological life support: resuscitation following cardiac arrest. Neurocrit Care 2012;17 Suppl 1:S21–S28. van Zanten AR, Polderman KH. Blowing hot and cold? Skin counter warming to prevent shivering during therapeutic cooling. Crit Care Med 2009;37:2106–2108.
