THERAPEUTIC HYPOTHERMIA AND TEMPERATURE MANAGEMENT Volume 3, Number 2, 2013 ª Mary Ann Liebert, Inc. DOI: 10.1089/ther.2013.1508
Expert Panel Discussions
Temperature Management in Neurological and Neurosurgical Intensive Care Units Moderator: Patrick Kochanek, MD1 Participants: Ava Puccio, RN, PhD,2 Michael Diringer, MD,3 and Patrick Kochanek, MD1
Maintaining normothermia in the neurocritical care unit is becoming common practice throughout the world. On the basis of strong experimental and clinical data showing that elevations in temperature can worsen outcome, new protocols are being developed that limit temperature elevations that may themselves enhance a number of secondary injury mechanisms. A series of state-of-the-art lectures presented at the 3rd Annual Therapeutic Hypothermia and Temperature Management Meeting in Miami, Florida, brought together clinicians and scientists to discuss and debate this topic. This particular session concentrated on three areas of temperature control that appear to be providing caregivers the strategy to improve outcome measures. In the area of fever control in patients with traumatic brain injury, Dr. Ava Puccio, University of Pittsburgh, emphasizes from a nursing standpoint the unappreciated effects of fever in previous clinical studies. Fever management protocols, in addition to fever work-ups, should be active in various clinical units. In the area of maintaining normothermia in neurocritical care units, Dr. Michael Diringer, Washington University School of Medicine, emphasized that the treatment of fever may be a complex problem and some adaptive temperature responses may be beneficial when in response to infections. Thus, whether the increase in fever may be enhancing brain injury or representing a more positive response to fever is an area that needs to be highlighted. Dr. Patrick Kochanek, University of Pittsburgh, provided a summary of new studies in his laboratory on the impact of hyperthermia on inflammatory responses. Previous studies have stressed that temperature fluctuations after a central nervous system insult can have dramatic effects on inflammatory cascades. Dr. Kochanek indicated multiple windows of opportunity whereby temperature elevations can have profound effects on various clinically relevant outcomes, including histopathological damage within the hippocampus. This session had a very enlightening question-and-answer exchange, again highlighting the interest in using temperature management strategies along with therapeutic hypothermia in a variety of clinical conditions that may have profound effects on clinical outcome.
questions that we have to think about in terms of treating specific patient populations. Question: I really enjoyed both of the latter speakers, who raised some interesting points—sort of a conundrum. Dr. Diringer’s talk suggested that there are major systemic consequences of hyperthermia. In other words, suppressing inflammatory mechanisms might be harmful, but Dr. Kochanek’s talk suggests that we need to cool the brain. So where are we now with selective brain cooling? We know, for example, that the Walter Reed group is putting a lot of emphasis into this topic. Does either Drs. Kochanek or Diringer have any insights about that? Dr. Michael Diringer: I don’t have any specific direct information regarding selective brain cooling. Still, I’m really not clear on how one could effectively isolate brain cooling considering that 20% of the cardiac output goes through the brain. If your brain is cold, then as that blood goes through the cold brain, it’s going to get cooled. So the brain will act as a cooling sink for the rest of the body. Short-term you probably could cool the brain in isolation, but it’s not clear whether over the long-term you can get away with it. The rationale for selective brain cooling is to avoid the systemic complications. But, I think, we’ve gotten really good at dealing with the systemic issues, at least of the moderate hypothermia that is currently done; thus, it’s not clear whether the imperative for isolated brain cooling is quite the same as we thought it was. Dr. Patrick Kochanek: I might also comment on that. I think one of the things that is really interesting in this regard, and that you have raised, Dr. Bullock, is that it likely depends a lot on the disease. For instance, in cardiac arrest, we probably need to cool the whole body because there will be benefit, for example, with mild hypothermia on the brain but also in other organs exposed to ischemia/reperfusion. So I think if you have a global ischemic insult like cardiac arrest, cooling only the brain might not be as good. We may also have gotten a
Comment: The presentations this morning were outstanding. Thank you very much. Obviously, temperature management is something we can do today, but there are many important
Departments of 1Critical Care Medicine and 2Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. 3 Department of Neurology, Washington University School of Medicine, St. Louis, Missouri.
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42 little clue of that from the neonatal trials in hypoxic–ischemic encephalopathy (HIE), with the cool cap trial versus the systemic hypothermia trial. Although both cool cap and total body cooling did show some benefit in HIE, there are data to suggest that isolated head cooling may not protect deep brain structure as well as total body cooling. In traumatic brain injury (TBI), however, we’ve run into a lot of problems trying to make hypothermia work. You may be 100% right, Ross, in that it would be preferable to isolate and cool the brain in a TBI victim where, unlike a cardiac arrest victim, there is no total body ischemia and there is no need for myocardial protection. The only target is protecting the injured brain, but there may be deleterious side effects of hypothermia systemically because there isn’t any potential benefit outside of the central nervous system (CNS). So in that setting, if isolated brain cooling could be accomplished, it might be very interesting to test. Such an approach might be particularly useful in a specific subtype of TBI such as contusion. It might be that if we eliminated systemic hypothermia in TBI, we could eliminate side effects. The last thing I would say is that you mentioned the Walter Reed data, and Dr. Frank Tortella has shown that at least in rodent models if you just cool the brain in TBI, you can see really dramatic beneficial effects in his models of very severe TBI. So if you can obtain benefits in that model, you may see beneficial effects in other models as well with isolated brain cooling. So I think the concept is an interesting one. The practicality of implementing head cooling only is more challenging. Question: Dr. Puccio, you gave a very nice presentation about what you do routinely in your ICU. Some of us in the room are thinking about the need for standard operating procedures (SOPs) for therapeutic hypothermia or temperature maintenance. Do you think we are ready to start proposing SOPs for temperature management, for example, in select patient populations that we can advertise internationally? Would this strategy potentially help people use your experience and see how it works in their units? Dr. Ava Puccio: I do think we are ready for some fever management protocols. Each institution may need to adapt it to their ICU population with a common goal of minimizing fever. Our population in Pittsburgh Neurotrauma ICU is focused on severe TBI and is aggressive with a set point of 36.5C. SOPs dramatically assist in the implementation of temperature maintenance with standing orders in place upon admission to the unit. Therapeutic hypothermia in severe TBI has not been shown to be definitive in improving outcome in the multicenter National Acute Brain Injury Study: Hypothermia (NABISH) studies; however, in cardiac arrest, detailed SOPs are required to assure that temperature management is performed in a timely, consistent manner, addressing management concerns such as potassium replacement and rate of rewarming. We would like to be on the ‘‘cutting edge’’ for hypothermia in severe TBI in believing that there is a subpopulation that may benefit with moderate hypothermia such as the subdural hematoma population requiring emergent craniotomy. This is to be determined by a future clinical trial. Comment: I think these are excellent presentations, and they all point to the disease specificity, if you will, the benefits of hypothermia versus the risks of hyperthermia. But, Dr. Ko-
EXPERT PANEL DISCUSSION chanek, in that context you’ve shown very compellingly that hyperthermia with a huge contusional load is bad, at least in the inflammatory cascades. What do you predict would be the case in the context of diffuse axonal injury or diffuse brain injury where you would not have that huge contusional load. Do you think you see some type of exacerbation? Dr. Patrick Kochanek: I certainly think you would. I was really surprised by the report of Clifton et al. (2011) regarding the most recent hypothermia clinical trial, showing that with hypothermia, if anything, there was a trend toward worse outcomes in patients with diffuse injury and a significant benefit in contusion. There are plenty of data and certainly much of your own data have suggested that with diffuse axonal injury, hypothermia is protective. So, I have not been able to reconcile that and, I think, it is also interesting that you bring up this issue, because the concept of how bad hyperthermia is in that context is unclear. Related to your question is a really hot question right now; namely, in mild TBI, does hyperthermia have a deleterious effect? If you think about it, all the kids in high schools and colleges who are going to football and soccer training camps get concussions in the middle of summer, and so, if you have hyperthermia around the time of the insult and it is bad, it could have dramatic consequences. It could be an important contributor to the overall morbidity that we see. For example, if deleterious effects of neuroinflammation are triggered after contusion by hyperthermia, one could even postulate that it could impact chronic traumatic encephalopathy (CTE)—which is linked to neuroinflammation. Question: Well, thank you for your great thoughts. I have a question as some of us are doing clinical trials: What would you recommend on how to treat fever in the control groups? We now have this experience from Scandinavia that the control group had to be treated by catheter or surface cooling to control the fever. So what would you recommend as a standard fever treatment for our trials? Or would you recommend also giving technical fever treatment? Dr. Ava Puccio: The NABISH trials have shown that intercenter variances can occur. Moving forward, prospective clinical trials should provide tighter protocol control on ICU management in both test and control groups. Fever management in the control group, as well as within the test group after the selected period of hypothermia treatment, should be tightly managed. Tighter temperature control is better achieved with newer technology, such as intravascular cooling or energy transfer pads. Controlled rewarming following hypothermia treatment is also much more precise with newer technology and should be utilized. Question: Dr. Diringer, I’m really interested in your thoughts. Do you think there is still equipoise to do a clinical trial of temperature regulation independent of hypothermia in neurocritical care, say, outside of cardiac arrest? Dr. Michael Diringer: The most important thing in terms of picking a control group is to be really clear about your question. The question is what determines who the scientifically appropriate control group should be. So if your question is, is hypothermia better than standard management, then you
EXPERT PANEL DISCUSSION
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need to compare hypothermia to standard management. So that is your scientific issue. Now, your dilemma comes in when you define standard management. What does the community in which you are going to do this trial consider standard management? You are not going to get them to change what they think they should be doing. So if the standard is to treat fever aggressively, then you need to do the aggressive fever treatment in your control group. Do I think there is clinical equipoise? I have a sliding scale for the level of evidence that I’ll require, and, I think, given that, if you minimize the risk, you could advocate for treatment of fever without the definitive outcome trial; in the context of recognizing that, it would be impossible to do that trial. I think that most people believe that fever management is important and, one, they won’t participate in a trial that doesn’t include that or, two, they may have appropriate ethics concerns. So your ethics concerns really come down to, do you believe that this is helpful or not, and if you believe it is helpful, then ethically, you are obligated to provide it and can’t design a study in which you don’t provide it.
depending on when and/or where it is placed. I don’t think our studies have done anything more other than to suggest it’s a possibility, but it is important to further explore. Maybe spreading depression plays a role.
Question: Dr. Kochanek, I wanted to raise a point. I really enjoyed your inflammation data with the new endpoints that you’ve devised there. One of the intriguing things you have raised is that the timing of general anesthesia following TBI might be really important in itself. So everybody who takes care of TBI patients everyday faces the conundrum of when to allow these people to go for noncranial surgery. When do they go to the operating room to close a belly or to fix a femoral fracture? As far as I know, there is very little in the literature, but the literature does say it’s okay to do it within the first 24 hours if the patient is stable. But your data suggest that maybe the timing is really important as to when we do surgery. So do you have any ideas about that, or do we need to develop this further?
Dr. Patrick Kochanek: I agree. I think that the proposed brain–body interaction has been understudied. But I do want to get back to my original point on this, though, that I think there may be large differences between those types of interactions in TBI where there is only brain injury versus, say, cardiac arrest, where you have had a total body ischemic insult. So I think it is very important to consider each of these diseases as a different entity, and in stroke, issues such as atherosclerotic disease and diabetes could also magnify the inflammatory response. Whenever the physiology and the pathophysiology are likely different, inflammation and hypothermia should be examined specifically in each condition.
Dr. Patrick Kochanek: We really wrestled with this question. It forced us to essentially double the size of our study to determine whether we really did have an effect of hyperthermia. I think that the effect of anesthesia alone has really become a major player in the last few years because of the studies by John Olney and colleagues (Brambrink et al., 2012), in particular, on the effect of anesthesia on the developing brain. Initially there was skepticism. How could just exposing the developing brain to isoflurane for 6 hours cause neuronal death? It was suggested that because this work was first done in developing rats, and you really can’t monitor them well enough, the results were incorrect. The studies have now been done in primates with rigorous control, and it is pretty clear that some anesthetics, such as ketamine or isoflurane, can produce this effect. I think if you look back at older studies of isoflurane exposure in animals, the gene array of cell-signaling effects resulting from just anesthesia exposure is really quite remarkable. So I think we have underestimated what anesthesia alone might do in the injured brain. I don’t know if in an adult animal model the anesthesia effect seen in the developing brain could be in some way mimicked when there is an injury. It certainly appears that the brain temperature probe also has some effect. I do think that when one places a brain temperature probe, intracranial pressure (ICP) monitor, or a PbO2 electrode, there could be some detrimental effect
Comment: I found your study of assessing this widespread activation of inflammatory cells after TBI and their temperature sensitivity very interesting. There are a couple of points I would like to raise. In spinal cord injury, we are now thinking about how spinal cord injury could lead to systemic consequences that could translate into patient care. Although you isolated your study to the brain, it would be interesting to see how a focal brain injury would affect inflammatory cascades up and down the neuroaxis and even other organs such as kidney and lung. This brings us back to the multiorgan injury situation that many TBI patients have, and the effects of temperature management not just on brain function, which obviously is our focus in neuro-ICU, but also on how the other organs are doing. So I think this is a really critical observation, and we need to examine what these macrophages are doing in terms of secondary insults.
Dr. Michael Diringer: I just wanted to add, looking at this from a slightly different perspective, that you have to bear in mind that the brain has its fingers in every organ, for example, blood pressure control and the sympathetic outflow. The input to the renal nerve plays a key role in sodium regulation and other mechanisms. So depending upon the particular injury, you may have different brain regions or regions in the neuroaxis playing a role. The spinal cord clearly is a big player here that will affect the neural input to various other organs, and the overarching CNS modulation could then be either disrupted or lost. That can lead to alterations in function of which you need to be aware. Dr. Patrick Kochanek: There is one other question that we have thought about trying to address but haven’t. What duration of fever is deleterious after brain injury? I walk through the ICU and see how poorly we manage fever in pediatrics; we don’t have either specifically designed servo-controlled cooling blankets or cooling catheters scaled down for children. Sure, it’s easier to cool a child than an adult with conventional methods, but fevers are very common in the pediatric ICU. So the idea of whether you really need to meticulously prevent them in the setting of brain injury versus respond to them remains unclear, but certainly it is a clinically relevant question. If 15 or 20 minutes is as bad as 2 hours, that would be important to know. We just don’t know the answer.
44 Comment: The question regarding the consequence of repetitive insults to the injured brain or spinal cord is also critical in terms of anesthetics, where infants may undergo repetitive operations to repair their heart, for example. During neuronal development, repetitive use of anesthetics may have cumulative harmful effects, and there are clinical studies on that subject. The same thing may apply to episodes of fever. It is not that a patient has one fever for 2 hours like we study in the experimental laboratory, but they can have repetitive febrile insults over several days and again the cumulative effect of those could be quite critical. Dr. Michael Diringer: Yes, I think that Dr. Kochanek’s point raises a fundamental issue about how we might approach clinical management of these patients. The usual thing to do is wait for a problem to develop and then act: Oh! I need to do something. It’s your trigger. It’s called pro re nata (PRN) medication. In PRN agitation, well, you are guaranteeing that the patient is going to become agitated before s/he is treated. In PRN nausea, we insist that patients become nauseated again before we treat them. So fever is the same deal. We wait for the first fever that your data suggest may have already done its job, and then we try to control it. So identifying subgroups in which prophylactic temperature modulation to prevent fevers may be an interesting direction. That might be a study that could be done in comparison to standard fever management to get past the ethics issue. When considering two different approaches to fever management, prophylactic versus reactive might be another way to look at this. Dr. Ava Puccio: From a nursing standpoint, I think the concern is the delay in correcting the fever after it has occurred. By using a lower fever set point, fever management can begin earlier in the cascade to avoid higher peak temperatures. Time is of the essence, since I do believe that multiple febrile episodes affect outcomes. This has been shown in the literature, with fever increasing hospital and ICU length-of-stays and resulting in poorer neurological outcomes in neurocritical care populations. Correcting fever in a timely manner or implementing a fever management protocol is important to minimize these effects. SOPs could minimize this. Question: One of the major targets to consider after brain injury is brain swelling and increases in ICP. What are the current data in terms of brain post-traumatic hyperthermia and ICP regulation? Dr. Michael Diringer: So there have been a number of studies that looked at temperature and ICP control. They show that, yes, you can control ICP if you lower the temperature. You’ll bring it down if you start at a high temperature and you cool the patient: lower the fever, the ICP will come down. There are a number of studies that also say that if you induce moderate hypothermia, you can help control ICP. I think it’s basically analogous to barbiturates. They work through the same mechanism: they slow down metabolism. Still, hypothermia also shares with barbiturates the same dilemma, which is, you control the ICP but it doesn’t look like you change the outcome. So the studies to date have just looked at ICP control and have not carried it beyond to look at outcome. But I think that as a third-tier therapy for ICP management, it is right
EXPERT PANEL DISCUSSION there equivalent with barbiturates in terms of how you should think about it and when you might choose to use it. Comment: To add to that, hypothermia probably has a better risk profile and better side-effect profile than the use of barbiturates. Dr. Michael Diringer: Yes, I agree. If I’m going down that path, we always will choose temperature regulation rather than barbiturates. Question: So we’ve heard today about temperature affecting inflammatory cascades and ICP. One of the first temperaturesensitive pathomechanisms we studied was inflammation because of its potential effects on brain swelling. Current data indicate that ICP elevations can be highly variable from patient to patient in terms of severity, duration, when they occur, and when they go away. Maybe ICP alterations are something to think about as we consider windows for normothermic regulation of the postinjured brain. Dr. John Povlishock and Enoch Wei have conducted a number of vascular reactivity studies with temperature after experimental TBI. Dr. Povlishock, have you assessed the effects of posttraumatic hyperthermia in the setting of posttraumatic vascular activity? Comment: Thanks, Dr. Dietrich, for putting us on the spot. Enoch and I were scratching our heads. You know, we’ve never done hyperthermia. Hypothermia, yes, but not hyperthermia. The only interesting comment I have, and we’ll present that data tomorrow, is this issue of repetitive injury, which, as you point out, is really hot on everybody’s radar screen. Interestingly, in the repetitive injury, even with very mild repetitive injuries, you can see profound exacerbation if you use very mild hypothermia in those animals; in those animal studies that are experiencing the repetitive injury, they are immensely protective. So there is some very intriguing evidence again about hypothermia and repetitive episodes of injury—in this case, trauma but perhaps other forms of perturbation. Question: With respect to the equipoise that we may or may not be at with regard to temperature control and fever, some of the historical data, I remember reading awhile back, was a Gordon Bernard Study on ibuprofen and sepsis that was reported as ‘‘no benefit.’’ Looking closer at the data, I think the clinical improvement, at least on some of the endpoints if not the primary endpoint, was actually pretty impressive, although perhaps underpowered to reach statistical significance. Could that be the case with other data out there as well? That maybe the power wasn’t quite there to show the difference, but, you know, looking at the absolute improvement, there was something that suggests that maybe a greater sample size with greater power would have shown an effect? Dr. Michael Diringer: I think you are asking a fundamental question about interpretation of clinical studies, because it’s one we face all the time. Most of our studies, except for the super-huge trials, are underpowered for clinical outcome. They have adequate power for an intermediate outcome that may be met, but usually there is no clear benefit for clinical outcome. How is the study interpreted? The nonbelievers say, ‘‘See it doesn’t work!’’ The believers say, ‘‘No, we are
EXPERT PANEL DISCUSSION underpowered, and it really does help because the other intermediate endpoints look promising.’’ I think that is where you are. You vote with your preconceived ideas, and then you look at it one way or the other way. Because you could be right, they could be right. Dr. Patrick Kochanek: I would just say that I totally agree, and obviously one strategy is to conduct large trials, but then the other strategy is to do what Professor Fritz Sterz did in the European multicenter hypothermia and ventricular fibrillation (VF) cardiac arrest trial. In that study, more than 3,000 patients were recruited and then whittled down to randomizing a few hundred with very carefully selected patients with VF cardiac arrest. They were successful with that approach. I guess that the analog in TBI would be to stratify by initial computed tomography (CT) in a similar manner with a reasonable size. That may be the way to get around the power issue because I agree that almost everything that has been done is underpowered. Question: What was dramatic in your presentation, Dr. Kochanek, and hopefully we will see part of that interesting series of studies in our Therapeutic Hypothermia and Temperature Management journal, was a big difference between CAl and CA3 vulnerability at 24 hours with hyperthermia. What we usually think about after brain trauma is that the CA3 vulnerability may be associated with classical excitotoxic or TBI-induced changes or deafferentation syndromes, but the CAl vulnerability is usually thought of as an ischemic process. Of course, the CAl hippocampal region is very close to your primary contusion site in your model. Do you have any thoughts about the difference in the vulnerability patterns you see with post-traumatic hyperthermia, because that is a really interesting and dramatic finding? Dr. Patrick Kochanek: I think a lot of it has to do with the model. Whether CAl and CA3 die in our model or just CA3 depends on many factors, such as the severity of the injury and/or the secondary insults. Thus, the level of injury severity that we select is also important. So, it is always difficult to determine because, in the controlled cortical impact (CCI) model, it’s very highly dependent on the injury severity. Key References from Panel Participants Aiyaga’ri V, Diringer MN. Fever control and its impact on outcomes: what is the evidence? J Neurol Sci 2007;261:39–46. Alam HB, Pusateri AE, Kindzelski A, Egan D, Hoots K, Andrews MT, Rhee P, Tisherman S, Mann K, Vostal J, Kochanek PM, Scalea T, Deal V, Sheppard F, Sopko G; HYPOSTAT workshop participants. Hypothermia and hemostasis in severe trauma: a new crossroads workshop report. J Trauma Acute Care Surg 2012;73:809–817. Axelrod YK, Diringer MN. Temperature management in acute neurologic disorders. Crit Care Clin 2006;22:767–785. Axelrod YK, Diringer MN. Temperature management in acute neurologic disorders. Neurol Clin 2008;26:585–603. Brambrink AM, Evers AS, Avidan MS, Farber NB, Smith DJ, Martin LD, Dissen GA, Creeley CE, Olney JW. Ketamineinduced neuroapoptosis in the fetal and neonatal rhesus macaque brain. Anesthesiology 2012;116:372–384. Clifton GL, Valadka A, Zygun D, Coffey CS, Drever P, Fourwinds S, Janis LS, Wilde E, Taylor P, Harshman K, Conley A,
45 Puccio A, Levin HS, McCauley SR, Bucholz RD, Smith KR, Schmidt JH, Scott JN, Yonas H, Okonkwo DO. Very early hypothermia induction in patients with severe brain injury (the National Acute Brain Injury Study: Hypothermia II): a randomised trial. Lancet Neurol 2011;10:131–139. Corry JJ, Dhar R, Murphy T, Diringer MN. Hypothermia for refractory status epilepticus. Neurocrit Care 2008;9:189–197. Drabek T, Kochanek PM. Therapeutic hypothermia on its 10th anniversary: is it time to turn the thermostat down? Circulation 2012;126:2803–2805. Empey PE, Miller TM, Philbrick AH, Melick JA, Kochanek PM, Poloyac SM. Mild hypothermia decreases fentanyl and midazolam steady-state clearance in a rat model of cardiac arrest. Crit Care Med 2012;40:1221–1228. Fink EL, Kochanek PM, Clark RS, Bell MJ. Fever control and application of hypothermia using intravenous cold saline. Pediatr Crit Care Med 2012;13:80–84. Hartings JA, Bullock MR, Okonkwo DO, Murray LS, Murray GD, Fabricius M, Maas AI, Woitzik J, Sakowitz O, Mathern B, Roozenbeek B, Lingsma H, Dreier JP, Puccio AM, Shutter LA, Pahl C, Strong AJ; Co-Operative Study on Brain Injury Depolarisations. Spreading depolarisations and outcome after traumatic brain injury: a prospective observational study. Lancet Neurol 2011;10:1058–1064. Hostler D, Zhou J, Tortorici MA, Bies RR, Rittenberger JC, Empey PE, Kochanek PM, Callaway CW, Poloyac SM. Mild hypothermia alters midazolam pharmacokinetics in normal healthy volunteers. Drug Metab Dispos 2010;38:781–788. Kochanek PM. Bakken lecture: the brain, the heart, and therapeutic hypothermia. Cleve Clin J Med 2009;76 Suppl2: S8–S12. Okonkwo DO, Yue JK, Puccio AM, Panczykowski D, Inoue T, McMahon PJ, Sorani MD, Yuh EL, Lingsma H, Maas A, Valadka A, Manley GT. GFAP-BDP as an acute diagnostic marker in traumatic brain injury: results from the prospective TRACK-TBI study. J Neurotrauma 2013. [Epub ahead of print] Puccio AM, Fischer MR, Jankowitz BT, Yonas H, Darby JM, Okonkwo DO. Induced normothermia attenuates intracranial hypertension and reduces fever burden after severe traumatic brain injury. Neurocrit Care 2009;11:82–87. Ray WZ, Diringer MN, Moran CJ, Zipfel GJ. Early endovascular coiling of posterior communicating artery saccular aneurysm in the setting of Staphylococcus bacteremia: case report and review of the literature. Neurosurgery 2010;66:E847. Scaravilli V, Tinchero G, Citerio G; Participants in the International Multi-Disciplinary Consensus Conference on the Critical Care Management of Subarachnoid Hemorrhage. Fever management in SAH. Neurocrit Care 2011;15:287–294. Smith CM, Adelson PD, Chang YF, Brown SD, Kochanek PM, Clark RS, Bayir H, Hinchberger J, Bell MJ. Brain-systemic temperature gradient is temperature-dependent in children with severe traumatic brain injury. Pediatr Crit Care Med 2011;12:449–454. Thampatty BP, Klamerus MM, Oberly PJ, Feldman KL, Bell MJ, Tyler-Kabara EC, Adelson PD, Clark RS, Kochanek PM, Poloyac SM. Hypothermia decreases cerebrospinal fluid asymmetric dimethylarginine levels in children with traumatic brain injury. Pediatr Crit Care Med 2013;14:403–412. Wagner AK, Bayir H, RenD, Puccio A, Zafonte RD, Kochanek PM. Relationships between cerebrospinal fluid markers of excitotoxicity, ischemia, and oxidative damage after severe TBI: the impact of gender, age, and hypothermia. J Neurotrauma 2004;21:125–136.
Expert Panel Discussions
Temperature Management in Neurological and Neurosurgical Intensive Care Units Moderator: Patrick Kochanek, MD1 Participants: Ava Puccio, RN, PhD,2 Michael Diringer, MD,3 and Patrick Kochanek, MD1
Maintaining normothermia in the neurocritical care unit is becoming common practice throughout the world. On the basis of strong experimental and clinical data showing that elevations in temperature can worsen outcome, new protocols are being developed that limit temperature elevations that may themselves enhance a number of secondary injury mechanisms. A series of state-of-the-art lectures presented at the 3rd Annual Therapeutic Hypothermia and Temperature Management Meeting in Miami, Florida, brought together clinicians and scientists to discuss and debate this topic. This particular session concentrated on three areas of temperature control that appear to be providing caregivers the strategy to improve outcome measures. In the area of fever control in patients with traumatic brain injury, Dr. Ava Puccio, University of Pittsburgh, emphasizes from a nursing standpoint the unappreciated effects of fever in previous clinical studies. Fever management protocols, in addition to fever work-ups, should be active in various clinical units. In the area of maintaining normothermia in neurocritical care units, Dr. Michael Diringer, Washington University School of Medicine, emphasized that the treatment of fever may be a complex problem and some adaptive temperature responses may be beneficial when in response to infections. Thus, whether the increase in fever may be enhancing brain injury or representing a more positive response to fever is an area that needs to be highlighted. Dr. Patrick Kochanek, University of Pittsburgh, provided a summary of new studies in his laboratory on the impact of hyperthermia on inflammatory responses. Previous studies have stressed that temperature fluctuations after a central nervous system insult can have dramatic effects on inflammatory cascades. Dr. Kochanek indicated multiple windows of opportunity whereby temperature elevations can have profound effects on various clinically relevant outcomes, including histopathological damage within the hippocampus. This session had a very enlightening question-and-answer exchange, again highlighting the interest in using temperature management strategies along with therapeutic hypothermia in a variety of clinical conditions that may have profound effects on clinical outcome.
questions that we have to think about in terms of treating specific patient populations. Question: I really enjoyed both of the latter speakers, who raised some interesting points—sort of a conundrum. Dr. Diringer’s talk suggested that there are major systemic consequences of hyperthermia. In other words, suppressing inflammatory mechanisms might be harmful, but Dr. Kochanek’s talk suggests that we need to cool the brain. So where are we now with selective brain cooling? We know, for example, that the Walter Reed group is putting a lot of emphasis into this topic. Does either Drs. Kochanek or Diringer have any insights about that? Dr. Michael Diringer: I don’t have any specific direct information regarding selective brain cooling. Still, I’m really not clear on how one could effectively isolate brain cooling considering that 20% of the cardiac output goes through the brain. If your brain is cold, then as that blood goes through the cold brain, it’s going to get cooled. So the brain will act as a cooling sink for the rest of the body. Short-term you probably could cool the brain in isolation, but it’s not clear whether over the long-term you can get away with it. The rationale for selective brain cooling is to avoid the systemic complications. But, I think, we’ve gotten really good at dealing with the systemic issues, at least of the moderate hypothermia that is currently done; thus, it’s not clear whether the imperative for isolated brain cooling is quite the same as we thought it was. Dr. Patrick Kochanek: I might also comment on that. I think one of the things that is really interesting in this regard, and that you have raised, Dr. Bullock, is that it likely depends a lot on the disease. For instance, in cardiac arrest, we probably need to cool the whole body because there will be benefit, for example, with mild hypothermia on the brain but also in other organs exposed to ischemia/reperfusion. So I think if you have a global ischemic insult like cardiac arrest, cooling only the brain might not be as good. We may also have gotten a
Comment: The presentations this morning were outstanding. Thank you very much. Obviously, temperature management is something we can do today, but there are many important
Departments of 1Critical Care Medicine and 2Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. 3 Department of Neurology, Washington University School of Medicine, St. Louis, Missouri.
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42 little clue of that from the neonatal trials in hypoxic–ischemic encephalopathy (HIE), with the cool cap trial versus the systemic hypothermia trial. Although both cool cap and total body cooling did show some benefit in HIE, there are data to suggest that isolated head cooling may not protect deep brain structure as well as total body cooling. In traumatic brain injury (TBI), however, we’ve run into a lot of problems trying to make hypothermia work. You may be 100% right, Ross, in that it would be preferable to isolate and cool the brain in a TBI victim where, unlike a cardiac arrest victim, there is no total body ischemia and there is no need for myocardial protection. The only target is protecting the injured brain, but there may be deleterious side effects of hypothermia systemically because there isn’t any potential benefit outside of the central nervous system (CNS). So in that setting, if isolated brain cooling could be accomplished, it might be very interesting to test. Such an approach might be particularly useful in a specific subtype of TBI such as contusion. It might be that if we eliminated systemic hypothermia in TBI, we could eliminate side effects. The last thing I would say is that you mentioned the Walter Reed data, and Dr. Frank Tortella has shown that at least in rodent models if you just cool the brain in TBI, you can see really dramatic beneficial effects in his models of very severe TBI. So if you can obtain benefits in that model, you may see beneficial effects in other models as well with isolated brain cooling. So I think the concept is an interesting one. The practicality of implementing head cooling only is more challenging. Question: Dr. Puccio, you gave a very nice presentation about what you do routinely in your ICU. Some of us in the room are thinking about the need for standard operating procedures (SOPs) for therapeutic hypothermia or temperature maintenance. Do you think we are ready to start proposing SOPs for temperature management, for example, in select patient populations that we can advertise internationally? Would this strategy potentially help people use your experience and see how it works in their units? Dr. Ava Puccio: I do think we are ready for some fever management protocols. Each institution may need to adapt it to their ICU population with a common goal of minimizing fever. Our population in Pittsburgh Neurotrauma ICU is focused on severe TBI and is aggressive with a set point of 36.5C. SOPs dramatically assist in the implementation of temperature maintenance with standing orders in place upon admission to the unit. Therapeutic hypothermia in severe TBI has not been shown to be definitive in improving outcome in the multicenter National Acute Brain Injury Study: Hypothermia (NABISH) studies; however, in cardiac arrest, detailed SOPs are required to assure that temperature management is performed in a timely, consistent manner, addressing management concerns such as potassium replacement and rate of rewarming. We would like to be on the ‘‘cutting edge’’ for hypothermia in severe TBI in believing that there is a subpopulation that may benefit with moderate hypothermia such as the subdural hematoma population requiring emergent craniotomy. This is to be determined by a future clinical trial. Comment: I think these are excellent presentations, and they all point to the disease specificity, if you will, the benefits of hypothermia versus the risks of hyperthermia. But, Dr. Ko-
EXPERT PANEL DISCUSSION chanek, in that context you’ve shown very compellingly that hyperthermia with a huge contusional load is bad, at least in the inflammatory cascades. What do you predict would be the case in the context of diffuse axonal injury or diffuse brain injury where you would not have that huge contusional load. Do you think you see some type of exacerbation? Dr. Patrick Kochanek: I certainly think you would. I was really surprised by the report of Clifton et al. (2011) regarding the most recent hypothermia clinical trial, showing that with hypothermia, if anything, there was a trend toward worse outcomes in patients with diffuse injury and a significant benefit in contusion. There are plenty of data and certainly much of your own data have suggested that with diffuse axonal injury, hypothermia is protective. So, I have not been able to reconcile that and, I think, it is also interesting that you bring up this issue, because the concept of how bad hyperthermia is in that context is unclear. Related to your question is a really hot question right now; namely, in mild TBI, does hyperthermia have a deleterious effect? If you think about it, all the kids in high schools and colleges who are going to football and soccer training camps get concussions in the middle of summer, and so, if you have hyperthermia around the time of the insult and it is bad, it could have dramatic consequences. It could be an important contributor to the overall morbidity that we see. For example, if deleterious effects of neuroinflammation are triggered after contusion by hyperthermia, one could even postulate that it could impact chronic traumatic encephalopathy (CTE)—which is linked to neuroinflammation. Question: Well, thank you for your great thoughts. I have a question as some of us are doing clinical trials: What would you recommend on how to treat fever in the control groups? We now have this experience from Scandinavia that the control group had to be treated by catheter or surface cooling to control the fever. So what would you recommend as a standard fever treatment for our trials? Or would you recommend also giving technical fever treatment? Dr. Ava Puccio: The NABISH trials have shown that intercenter variances can occur. Moving forward, prospective clinical trials should provide tighter protocol control on ICU management in both test and control groups. Fever management in the control group, as well as within the test group after the selected period of hypothermia treatment, should be tightly managed. Tighter temperature control is better achieved with newer technology, such as intravascular cooling or energy transfer pads. Controlled rewarming following hypothermia treatment is also much more precise with newer technology and should be utilized. Question: Dr. Diringer, I’m really interested in your thoughts. Do you think there is still equipoise to do a clinical trial of temperature regulation independent of hypothermia in neurocritical care, say, outside of cardiac arrest? Dr. Michael Diringer: The most important thing in terms of picking a control group is to be really clear about your question. The question is what determines who the scientifically appropriate control group should be. So if your question is, is hypothermia better than standard management, then you
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need to compare hypothermia to standard management. So that is your scientific issue. Now, your dilemma comes in when you define standard management. What does the community in which you are going to do this trial consider standard management? You are not going to get them to change what they think they should be doing. So if the standard is to treat fever aggressively, then you need to do the aggressive fever treatment in your control group. Do I think there is clinical equipoise? I have a sliding scale for the level of evidence that I’ll require, and, I think, given that, if you minimize the risk, you could advocate for treatment of fever without the definitive outcome trial; in the context of recognizing that, it would be impossible to do that trial. I think that most people believe that fever management is important and, one, they won’t participate in a trial that doesn’t include that or, two, they may have appropriate ethics concerns. So your ethics concerns really come down to, do you believe that this is helpful or not, and if you believe it is helpful, then ethically, you are obligated to provide it and can’t design a study in which you don’t provide it.
depending on when and/or where it is placed. I don’t think our studies have done anything more other than to suggest it’s a possibility, but it is important to further explore. Maybe spreading depression plays a role.
Question: Dr. Kochanek, I wanted to raise a point. I really enjoyed your inflammation data with the new endpoints that you’ve devised there. One of the intriguing things you have raised is that the timing of general anesthesia following TBI might be really important in itself. So everybody who takes care of TBI patients everyday faces the conundrum of when to allow these people to go for noncranial surgery. When do they go to the operating room to close a belly or to fix a femoral fracture? As far as I know, there is very little in the literature, but the literature does say it’s okay to do it within the first 24 hours if the patient is stable. But your data suggest that maybe the timing is really important as to when we do surgery. So do you have any ideas about that, or do we need to develop this further?
Dr. Patrick Kochanek: I agree. I think that the proposed brain–body interaction has been understudied. But I do want to get back to my original point on this, though, that I think there may be large differences between those types of interactions in TBI where there is only brain injury versus, say, cardiac arrest, where you have had a total body ischemic insult. So I think it is very important to consider each of these diseases as a different entity, and in stroke, issues such as atherosclerotic disease and diabetes could also magnify the inflammatory response. Whenever the physiology and the pathophysiology are likely different, inflammation and hypothermia should be examined specifically in each condition.
Dr. Patrick Kochanek: We really wrestled with this question. It forced us to essentially double the size of our study to determine whether we really did have an effect of hyperthermia. I think that the effect of anesthesia alone has really become a major player in the last few years because of the studies by John Olney and colleagues (Brambrink et al., 2012), in particular, on the effect of anesthesia on the developing brain. Initially there was skepticism. How could just exposing the developing brain to isoflurane for 6 hours cause neuronal death? It was suggested that because this work was first done in developing rats, and you really can’t monitor them well enough, the results were incorrect. The studies have now been done in primates with rigorous control, and it is pretty clear that some anesthetics, such as ketamine or isoflurane, can produce this effect. I think if you look back at older studies of isoflurane exposure in animals, the gene array of cell-signaling effects resulting from just anesthesia exposure is really quite remarkable. So I think we have underestimated what anesthesia alone might do in the injured brain. I don’t know if in an adult animal model the anesthesia effect seen in the developing brain could be in some way mimicked when there is an injury. It certainly appears that the brain temperature probe also has some effect. I do think that when one places a brain temperature probe, intracranial pressure (ICP) monitor, or a PbO2 electrode, there could be some detrimental effect
Comment: I found your study of assessing this widespread activation of inflammatory cells after TBI and their temperature sensitivity very interesting. There are a couple of points I would like to raise. In spinal cord injury, we are now thinking about how spinal cord injury could lead to systemic consequences that could translate into patient care. Although you isolated your study to the brain, it would be interesting to see how a focal brain injury would affect inflammatory cascades up and down the neuroaxis and even other organs such as kidney and lung. This brings us back to the multiorgan injury situation that many TBI patients have, and the effects of temperature management not just on brain function, which obviously is our focus in neuro-ICU, but also on how the other organs are doing. So I think this is a really critical observation, and we need to examine what these macrophages are doing in terms of secondary insults.
Dr. Michael Diringer: I just wanted to add, looking at this from a slightly different perspective, that you have to bear in mind that the brain has its fingers in every organ, for example, blood pressure control and the sympathetic outflow. The input to the renal nerve plays a key role in sodium regulation and other mechanisms. So depending upon the particular injury, you may have different brain regions or regions in the neuroaxis playing a role. The spinal cord clearly is a big player here that will affect the neural input to various other organs, and the overarching CNS modulation could then be either disrupted or lost. That can lead to alterations in function of which you need to be aware. Dr. Patrick Kochanek: There is one other question that we have thought about trying to address but haven’t. What duration of fever is deleterious after brain injury? I walk through the ICU and see how poorly we manage fever in pediatrics; we don’t have either specifically designed servo-controlled cooling blankets or cooling catheters scaled down for children. Sure, it’s easier to cool a child than an adult with conventional methods, but fevers are very common in the pediatric ICU. So the idea of whether you really need to meticulously prevent them in the setting of brain injury versus respond to them remains unclear, but certainly it is a clinically relevant question. If 15 or 20 minutes is as bad as 2 hours, that would be important to know. We just don’t know the answer.
44 Comment: The question regarding the consequence of repetitive insults to the injured brain or spinal cord is also critical in terms of anesthetics, where infants may undergo repetitive operations to repair their heart, for example. During neuronal development, repetitive use of anesthetics may have cumulative harmful effects, and there are clinical studies on that subject. The same thing may apply to episodes of fever. It is not that a patient has one fever for 2 hours like we study in the experimental laboratory, but they can have repetitive febrile insults over several days and again the cumulative effect of those could be quite critical. Dr. Michael Diringer: Yes, I think that Dr. Kochanek’s point raises a fundamental issue about how we might approach clinical management of these patients. The usual thing to do is wait for a problem to develop and then act: Oh! I need to do something. It’s your trigger. It’s called pro re nata (PRN) medication. In PRN agitation, well, you are guaranteeing that the patient is going to become agitated before s/he is treated. In PRN nausea, we insist that patients become nauseated again before we treat them. So fever is the same deal. We wait for the first fever that your data suggest may have already done its job, and then we try to control it. So identifying subgroups in which prophylactic temperature modulation to prevent fevers may be an interesting direction. That might be a study that could be done in comparison to standard fever management to get past the ethics issue. When considering two different approaches to fever management, prophylactic versus reactive might be another way to look at this. Dr. Ava Puccio: From a nursing standpoint, I think the concern is the delay in correcting the fever after it has occurred. By using a lower fever set point, fever management can begin earlier in the cascade to avoid higher peak temperatures. Time is of the essence, since I do believe that multiple febrile episodes affect outcomes. This has been shown in the literature, with fever increasing hospital and ICU length-of-stays and resulting in poorer neurological outcomes in neurocritical care populations. Correcting fever in a timely manner or implementing a fever management protocol is important to minimize these effects. SOPs could minimize this. Question: One of the major targets to consider after brain injury is brain swelling and increases in ICP. What are the current data in terms of brain post-traumatic hyperthermia and ICP regulation? Dr. Michael Diringer: So there have been a number of studies that looked at temperature and ICP control. They show that, yes, you can control ICP if you lower the temperature. You’ll bring it down if you start at a high temperature and you cool the patient: lower the fever, the ICP will come down. There are a number of studies that also say that if you induce moderate hypothermia, you can help control ICP. I think it’s basically analogous to barbiturates. They work through the same mechanism: they slow down metabolism. Still, hypothermia also shares with barbiturates the same dilemma, which is, you control the ICP but it doesn’t look like you change the outcome. So the studies to date have just looked at ICP control and have not carried it beyond to look at outcome. But I think that as a third-tier therapy for ICP management, it is right
EXPERT PANEL DISCUSSION there equivalent with barbiturates in terms of how you should think about it and when you might choose to use it. Comment: To add to that, hypothermia probably has a better risk profile and better side-effect profile than the use of barbiturates. Dr. Michael Diringer: Yes, I agree. If I’m going down that path, we always will choose temperature regulation rather than barbiturates. Question: So we’ve heard today about temperature affecting inflammatory cascades and ICP. One of the first temperaturesensitive pathomechanisms we studied was inflammation because of its potential effects on brain swelling. Current data indicate that ICP elevations can be highly variable from patient to patient in terms of severity, duration, when they occur, and when they go away. Maybe ICP alterations are something to think about as we consider windows for normothermic regulation of the postinjured brain. Dr. John Povlishock and Enoch Wei have conducted a number of vascular reactivity studies with temperature after experimental TBI. Dr. Povlishock, have you assessed the effects of posttraumatic hyperthermia in the setting of posttraumatic vascular activity? Comment: Thanks, Dr. Dietrich, for putting us on the spot. Enoch and I were scratching our heads. You know, we’ve never done hyperthermia. Hypothermia, yes, but not hyperthermia. The only interesting comment I have, and we’ll present that data tomorrow, is this issue of repetitive injury, which, as you point out, is really hot on everybody’s radar screen. Interestingly, in the repetitive injury, even with very mild repetitive injuries, you can see profound exacerbation if you use very mild hypothermia in those animals; in those animal studies that are experiencing the repetitive injury, they are immensely protective. So there is some very intriguing evidence again about hypothermia and repetitive episodes of injury—in this case, trauma but perhaps other forms of perturbation. Question: With respect to the equipoise that we may or may not be at with regard to temperature control and fever, some of the historical data, I remember reading awhile back, was a Gordon Bernard Study on ibuprofen and sepsis that was reported as ‘‘no benefit.’’ Looking closer at the data, I think the clinical improvement, at least on some of the endpoints if not the primary endpoint, was actually pretty impressive, although perhaps underpowered to reach statistical significance. Could that be the case with other data out there as well? That maybe the power wasn’t quite there to show the difference, but, you know, looking at the absolute improvement, there was something that suggests that maybe a greater sample size with greater power would have shown an effect? Dr. Michael Diringer: I think you are asking a fundamental question about interpretation of clinical studies, because it’s one we face all the time. Most of our studies, except for the super-huge trials, are underpowered for clinical outcome. They have adequate power for an intermediate outcome that may be met, but usually there is no clear benefit for clinical outcome. How is the study interpreted? The nonbelievers say, ‘‘See it doesn’t work!’’ The believers say, ‘‘No, we are
EXPERT PANEL DISCUSSION underpowered, and it really does help because the other intermediate endpoints look promising.’’ I think that is where you are. You vote with your preconceived ideas, and then you look at it one way or the other way. Because you could be right, they could be right. Dr. Patrick Kochanek: I would just say that I totally agree, and obviously one strategy is to conduct large trials, but then the other strategy is to do what Professor Fritz Sterz did in the European multicenter hypothermia and ventricular fibrillation (VF) cardiac arrest trial. In that study, more than 3,000 patients were recruited and then whittled down to randomizing a few hundred with very carefully selected patients with VF cardiac arrest. They were successful with that approach. I guess that the analog in TBI would be to stratify by initial computed tomography (CT) in a similar manner with a reasonable size. That may be the way to get around the power issue because I agree that almost everything that has been done is underpowered. Question: What was dramatic in your presentation, Dr. Kochanek, and hopefully we will see part of that interesting series of studies in our Therapeutic Hypothermia and Temperature Management journal, was a big difference between CAl and CA3 vulnerability at 24 hours with hyperthermia. What we usually think about after brain trauma is that the CA3 vulnerability may be associated with classical excitotoxic or TBI-induced changes or deafferentation syndromes, but the CAl vulnerability is usually thought of as an ischemic process. Of course, the CAl hippocampal region is very close to your primary contusion site in your model. Do you have any thoughts about the difference in the vulnerability patterns you see with post-traumatic hyperthermia, because that is a really interesting and dramatic finding? Dr. Patrick Kochanek: I think a lot of it has to do with the model. Whether CAl and CA3 die in our model or just CA3 depends on many factors, such as the severity of the injury and/or the secondary insults. Thus, the level of injury severity that we select is also important. So, it is always difficult to determine because, in the controlled cortical impact (CCI) model, it’s very highly dependent on the injury severity. Key References from Panel Participants Aiyaga’ri V, Diringer MN. Fever control and its impact on outcomes: what is the evidence? J Neurol Sci 2007;261:39–46. Alam HB, Pusateri AE, Kindzelski A, Egan D, Hoots K, Andrews MT, Rhee P, Tisherman S, Mann K, Vostal J, Kochanek PM, Scalea T, Deal V, Sheppard F, Sopko G; HYPOSTAT workshop participants. Hypothermia and hemostasis in severe trauma: a new crossroads workshop report. J Trauma Acute Care Surg 2012;73:809–817. Axelrod YK, Diringer MN. Temperature management in acute neurologic disorders. Crit Care Clin 2006;22:767–785. Axelrod YK, Diringer MN. Temperature management in acute neurologic disorders. Neurol Clin 2008;26:585–603. Brambrink AM, Evers AS, Avidan MS, Farber NB, Smith DJ, Martin LD, Dissen GA, Creeley CE, Olney JW. Ketamineinduced neuroapoptosis in the fetal and neonatal rhesus macaque brain. Anesthesiology 2012;116:372–384. Clifton GL, Valadka A, Zygun D, Coffey CS, Drever P, Fourwinds S, Janis LS, Wilde E, Taylor P, Harshman K, Conley A,
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