THERAPEUTIC HYPOTHERMIA AND TEMPERATURE MANAGEMENT Volume 2, Number 3, 2012 ª Mary Ann Liebert, Inc. DOI: 10.1089/ther.2012.1512
Expert Panel Discussions
Temperature Management in Neurological and Neurosurgical Intensive Care Unit Moderator: W. Dalton Dietrich, Ph.D.1 Participants: David O. Okonkwo, M.D., Ph.D.,2 Mary Kay Bader, R.N., M.S.N.,3 and Colonel Rocco Armonda, M.D.4
A major use of therapeutic hypothermia and temperature management occurs within the neuroscience ICU units where state-of-theart imaging and monitoring equipment are used to evaluate injury mechanisms and targets for therapeutic interventions. Previous experimental and clinical studies have demonstrated the beneficial effects of mild hypothermia in terms of protecting the injured brain from secondary insults, as well as the importance of limiting periods of reactive hyperthermia in the post-injury setting. A series of stateof-the-art lectures presented at the 2nd Annual Therapeutic Hypothermia and Temperature Management Meeting in Miami brought together experts in the field of temperature management in neurological and neurosurgical intensive care units (ICU). Dr. David Okonkwo, Director of the Neurotrauma Program at the University of Pittsburgh discussed controversies in the use of hypothermia targeting traumatic brain injury (TBI). Dr. Okonkwo emphasized the recent results from the NABISH hypothermia trials as well as new diagnostic targets that could be used to guide temperature management strategies. Recently, the renewed interest in cortical spreading depolarization as a secondary insult has been emphasized. Importantly, these repetitive ionic insults in the postinjured brain appear to be extremely temperature sensitive and a potentially significant secondary insult that needs to be monitored and prevented. Mary Kay Bader, an Intensive Care Nurse and spokesperson for the use of temperature management strategies in various patient populations, presented an important presentation on nursing support in the ICU for hypothermic therapy. Mrs. Bader emphasized the need for established protocols to be followed in terms of the use of hypothermia and other critical care procedures that must be implemented to maximally improve outcome in various patient populations. The point that ‘‘champions’’ need to be identified to promote and lead the use of hypothermia in various hospital situations was emphasized, as well as the importance of experienced critical care nurses at the bedside to continuously monitor patient status. Dr. Colonel Rocco Armonda, Director of the Cerebrovascular Surgery and Interventional Neuroradiology at the Walter Reed Hospital, presented an important topic regarding cooling and subarachnoid hemorrhage (SAH) and vasospasm. Vasospasm is a potential consequence of SAH or trauma that can
lead to high morbidity and mortality. Recent studies have investigated underlying pathophysiological mechanisms for the generation of vasospasm as well as the effects of induced hypothermia or periods of hyperthermia on the frequency of vasospasm. New monitoring approaches are required to evaluate the hemodynamic status of tissue including the use of microdialysis to gauge degrees of vasospasm-induced ischemia. It is clear from these studies that the brain can have a critical influence on many biochemical and molecular mechanisms of injury that need to be monitored and evaluated at the bedside. Dr. Carmelo Graffagnino: A question regarding cortical spreading depression to the whole panel. Do you think that the spreading depression is a marker of ischemic severity and that hypothermia is protecting the injured brain, or do you think that there is also pathology created by the spreading depression and activation of the ischemic cortex and that hypothermia is tuning down the electrical function of the brain sufficiently to protect it from the damage produced by the spreading depression? What I worry about is whether electrophysiological alternating drugs like antiepileptics block spreading depression, and if so, do you think this would be a compounding effect in your clinical trials? Dr. David Okonkwo: So, those are great questions, and I’ll take the first step. With respect to the first point you brought up, from my perspective, it’s both. Spreading depression is both a reflection of the severity of the injury and a contribution to ongoing and worsening pathology. I say that for several reasons. If you remember one of Dr. Armonda’s slides, showing the relationship of fever to the occurrence of spreading depression, there is no reason for spreading depression to induce a fever. So, it should be in response to fever, setting the conditions for the increased potential for spreading depression to develop. But, by the same token, we also know, from Dr. Tony Strong’s perspective of spreading depression being a brain tsunami, that it leaves behind additional damage. This is over and above the fact that the more severely
1
Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, Florida. Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania. 3 Mission Hospital, Mission Viejo, California. 4 National Navy MEDCEN and Walter Reed Army MEDCEN, Bethesda, Maryland. 2
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EXPERT PANEL DISCUSSION injured you are, the more likely you are to develop spreading depression. The second question about the use of antiepileptics, we have not found an influence of the use of either Dilantin or Keppra on the overall incidence of spreading depression in the TBI population. However, I do not routinely take care of aneurysm patients anymore. Are you still using prophylactic antiepileptic therapy? Dr. Rocco Armonda: We actually avoid the use of Dilantin now because Dilantin actually has a worsening effect in most cases. We have gone to Keppra in selected patients. The patients that seem to be the highest risk for spreading depression scenarios in SAH are usually the poorer grade patients, higher blood burden. Patients who are elderly also have some higher incidence of seizures as well. Spreading depression is different from what we see in terms of postoperative or subarachnoid seizures. It’s a different entity. We think that perhaps spreading depression may explain this entity of microvascular spasm that we don’t necessarily see angiographically that may in fact lead to more of these encephalopathic global changes that are ongoing. It’s very hard to say if it is associative or causative for the patient’s deficit. Is it something that is just going to be associated with significant burden of injury or is it causing the burden of injury. Certainly, we see worse outcomes with those patients who have a higher incidence of spreading depression. More so than just their SAH grade. Dr. David Okonkwo: Our German collaborators with the COSBID group obtained absolute mountains of data from all of the centers looking at what had happened to these patients in the ICU that was not directed at the spreading depression. Assessing the use of antiepileptics, sedatives, and narcotics, they tried to map the use of all the pharmacologic agents. This is not a trivial exercise. And the only drug that had an influence on spreading depression was Ketamine. So now we understand two things that influence spreading depression: temperature and Ketamine. But none of the others had been shown to have a significant correlation with the incidence of spreading depression. Dr. Hans Friberg: I’m also thrilled and intrigued by this discussion about spreading depression. My background is a laboratory setting, and we induce spreading depression all the time—that’s no problem. I was not aware of the fact that this is maybe an important issue in the adult brain. Would this be important regardless of whether it’s a focal ischemic or a global brain ischemic insult, for example after cardiac arrest? The main issue, how do we monitor it? You already replied that there are big problems treating it, but do we monitor it with continuous EEG, or how do we do it? Dr. David Okonkwo: I wish Jed Hartings, Tony Strong, or other real experts in spreading depression could participate in answering these great questions. Here’s the thing. The problem in 2012 is the only way to monitor this is to place a strip electrode on the surface of the brain. Therefore we are restricted to patients who are participating in research protocols wherein a craniotomy is being performed for some other reason. We are not in a position to deploy this in a routine clinical scenario yet. Now, some investigators are working very hard to come up with a way to use surface electrodes to
105 actually capture spreading depression events. At a recent meeting I attended, pilot data were shown that were highly encouraging. But we are not quite sure whether we can actually capture these events in the absence of invasive monitoring placed on the surface of the brain. That’s number one. Number two is whether this is a focal or a global event. Almost by definition, you have to look at spreading depression as a focal event. That’s because it happens in specific scenarios. When we are assessing CSD in the setting of brain injury, we are actually intentionally placing the electrode next to what looks like a contused brain because we know that we are more likely to capture the events in a penumbral brain region adjacent to contused brain. The same concept is appropriate in stroke where you are targeting the penumbra because we know that that is where we are more likely to find these transient events occurring as opposed to somewhere remote in the brain away from the primary focus of ischemic injury. Is that the answer to your question? Dr. Dalton Dietrich: Yes, I think so. Dr. Rainer Kollmar: I have a question about SAH. We recently started to cool these patients with a high Fisher grade, and the objective for this was that they had an elevated intracrancial pressure (ICP). The question is whether the cooling treatment was affecting the severity of vasospasm. We are facing the problem of how to really measure this vasospasm if the patients are cooled. How are you doing your titration if for example, you rewarm with, say, plateau phases where these patients have vasospasm? What is your objective? Do you always transfer these patients to the angiography laboratory or are you using ultrasound? Dr. Rocco Armonda: We start with transcranial Dopplers (TCDs), and in the poorest grade patients we also have ongoing brain tissue oxygen monitoring. So you have brain tissue oxygen (PbtO2) and TCDs. The problem is that the TCDs are only useful if in fact they are high or if there is a significant change. So then we have patients that we may not be picking up conducting vessel vasospasm. So the third entity, which I’m very excited about that I think may be even more helpful, is continuous EEG. We have a select group of patients on whom we started continuous EEG but were unable to see evidence of distal ischemia. The problem is that, in some of these patients, you’ll do an angiogram, and they have fairly severe vasospasm without a big change in their PbtO2 because their leptomeningial circulation has basically compensated for that hemodynamic state. In other patients, you see no conducting vessel vasospasm of the superclinoid carotid, or middle cerebral artery (MCA). However, the microcirculation is in spasm or is being stressed, and they’ll have a drop in the PbtO2 with normal lung function, and we can’t explain it based on the TCDs. So I think it is very difficult depending upon the type of area of the circulation that is being affected: proximal, distal, or diffuse combine vasospasm, which by that point becomes more obvious and less responsive to treatment. So my advice is that if in fact you are dealing with somebody with whom you are using hypothermia and you are using it for ICP protection, certainly your ICP is going to give you an indicator of the rewarming period. Rewarming is usually where it is most dangerous for vasospasm and in stroke because there is poor perfusion to
106 hyperemia rebound. But if you titrate that to the PbtO2 or to TCD readings and continuous EEG, you will be less likely to be rewarming them in a period when they are in vasospasm. You have to individualize that patient’s rewarm schedule. In some patients where TCDs are unobtainable, you can basically have no indicator of vasospasm due to poor bone windows, but when you take them to angiography, they have severe spasm. Mary Kay Bader: Our approach is similar to Rocco’s. Our neurosurgeons will monitor CT angiograms (CTAs) to look at the vessels for vasospasm as they make decisions on whether it is time to start rewarming. We do not obtain CTAs daily but monitor them periodically to see if there is diffuse spasm. Dr. Rocco Armonda: CT perfusion is labor intensive, requiring transport and a large contrast load. So it is very difficult in terms of the timing. You’d like to have the ideal monitor. Maybe microdialysis would be the answer in terms of seeing whether these patients are in a metabolic crisis. We just don’t have a good enough monitor to say truly if a patient is in spasm or not. Dr. Karen Porth: Quantitative EEG? Dr. Rocco Armonda: Absolutely, yes, quantitative EEG—that you could track. So if you are tracking a patient before you put them into hypothermia and then during the cooling period, you can then follow them over an extended period. Dr. Karen Porth: I’m a vascular neurologist, and I was going to comment about quantitative EEG and doing that continuously. The other thing I was going to comment about is that Ketamine is my new drug of choice for status because for patients with vasospasm or who have SAH, and it’s really nice in vasospasm patients because it doesn’t cause hypotension. So that was interesting what you were saying about Ketamine not having an effect on cortical spreading depression. Dr. Rocco Armonda: Isn’t that a paradox? When you think about it, we all were brought up to think of Ketamine as lowering your seizure threshold, right? It has a reverse effect perhaps on spreading depression. Dr. Ross Bullock: We have an ongoing debate in our ICU with some of the intensivists about the fact that hypothermia may be harmful in terms of worsening pneumonia. Everybody knows that there are theoretical lab data that it suppresses immune function, and they cite to us some literature that shows that it has been shown to worsen pneumonia. ICU nurses are closest to that kind of information, so my question primarily for Mary Kay is what do you think about that debate? Mary Kay Bader: I think there is validity that they are at increased risk for ventilator-associated pneumonia and for Acute Respiratory Distress Syndrome (ARDS). Sometimes IV fluid intake increases insidiously 2 liters positive per day and the trend continues for 5 days. Suddenly the patient is 10 liters positive at 5 days and the team has not realized it. There are complications because of this trend. We focus in on aggressive patient turning, aggressive head of the bed up as much as
EXPERT PANEL DISCUSSION possible, percussion; we’ve even proned patients who are hypothermic if their lungs are getting worse. So it really takes the ICU nurse, the intensivist, and the respiratory therapist to all work together, but it is a serious problem. Sometimes you’ll hear nurses say that the patient’s ICP is just so high, I can’t turn them. Well, no, you have to turn them. Because if you lay that patient in the bed and don’t do anything, I guarantee you they are going to have a pulmonary problem. So it is about being very aggressive. Dr. Patrick Kochanek: Dave, I really enjoyed your lecture. I was wondering about a topic that is kind of a different angle on the findings that you have presented. You know there is a considerable body of data that says that hypothermia attenuates axonal injury in experimental models of TBI, yet the Clifton study showed the worsening of outcome in the patients with, if you want to call it, a diffuse axonal injury (DAI) type of profile. So I am interested in your thoughts on why you think hypothermia is actually deleterious rather than beneficial and the clinical angle on that. Dr. David Okonkwo: There is an important point about the NABISH studies that I don’t think gets discussed enough. This is one of the things that we appreciated as we were putting the papers together. Those studies were designed for hypothermia to be a primary neuroprotectant. This was a guess, just like the magnesium TBI study was a guess that turned out to be a very wrong guess of the dose of magnesium and it led to higher mortality. So there was a guess of the dose and time of hypothermia in this cooling study. I don’t think that the time of hypothermia in the NABISH studies of 48 hours is sufficient to take into account the pathology of the evolution of axonal injury that we’ve learned from John Povlishock over the years takes longer than that in the human to finish playing itself out. As we know, the Chinese study of hypothermia maintained hypothermia for much longer. If and when we do this third iteration of a multicenter hypothermia trial, duration of cooling will still be one of the critical remaining features for us to work. What will be our triggers to initiate rewarming as opposed to just a strict 48 hours and is it time to rewarm? We haven’t actually come to the right conclusion about that yet. But I think the dose and the time were wrong to target that patient population. Dr. Neeraj Badjatia: Just going back to the discussion about vasospasm and how to monitor for it. At Columbia, we’ve been doing what we call a neuromonitoring bundle where, in addition to Lycox and microdialysis, we place a CBF probe, a depth EEG, and surface EEG as well as a drug bulb just to get at this question of how can you better target and monitor an organ of interest, which is the brain. I’ve got to say, as much data as we’ve collected and we’ve learned, it’s very complicated obviously. What we think is that microdialysis measurements do help, but they doesn’t help by themselves. PbtO2 helps, but as you know it doesn’t help by itself. Surface EEG, while we had a lot of hope that it would be a vasospasm monitor, the reality is it’s a great spasm monitor in patients who aren’t moderately or deeply sedated. I think what we are talking about is that we’ve got these great physiological tools, but now we are actually at the point where we need to think about how to analyze and interpret the data in a meaningful way.
EXPERT PANEL DISCUSSION Dr. David Okonkwo: In real time? Dr. Neeraj Badjatia: Yes, in real time. That is exactly the case, for example, with the depth EEG monitor, I think, I was told about half a million minutes worth of EEG data that had to be coded in a way that you could analyze it. Our informatics department has just become like a Ph.D. project for a couple of graduate students now to analyze these data. So it is becoming an enormous amount of data, an enormous amount of analysis. It’s a whole different field, in a sense, this use of informatics to try and understand the readings. But getting back to the first question about how do we track in hypothermic patient spasms, we use all of the above that was mentioned. We use CT perfusion, we use our changes in alpha–delta ratios if we can watch those. I think microdialysis is really the best tissue marker that we have of metabolism during cooling at this point because we actually see significant changes during shivering that sometimes trigger us to look at the patient. Kind of the reverse of what you think about, but we see the changes on the monitors first. Dr. David Okonkwo: Where do you place the microdialysis probe? Dr. Neeraj Badjatia: In SAH patients, it tends to be on the side where there is more blood, if there is more blood on one side or the other. There is some talk about doing the reading on both sides, but we are now talking about already two to three burr holes on one side. At a certain point, you reach some limitation. So, I think microdialysis is really going to help us, although we’re several years away from really fully understanding how it is going to help us. But we are learning a lot at this point, and certainly with hypothermia, I think it is one of the ways for us to track spasms. In fact, we are doing it in our cardiac arrest patients too: to track when to rewarm and how long to cool somebody. Mary Kay’s point about fluid management is absolutely right. In our prospective data set that we have, we found that fluid management or mismanagement was an independent driver of morbidity to mortality. We are putting those data together right now. So I think this is an important aspect of hypothermia management. Dr. Ard Struijs: I’ve got three short questions. The first to Mary Kay. You mentioned on your slides that there is the high risk for venous embolism by cooling intervascularly. I’ve been doing it for more than 10 years, and I didn’t see this problem. Do you have more data about this? Mary Kay Bader: I don’t have any personal data because we do not use that system, but I have colleagues who have used intervascular systems and have spoken of the incidence of deep vein thrombosis (DVT) or venous thromboembolism. There are a few studies out there that have shown that it is a question of surveillance, I think. Do we look for it? Are we routinely screening our patients for that? So if you don’t see it, if you are not monitoring or screening for it, is it not happening? It is one of the risks that have been identified in the literature. There are risks to each system. But, I have had colleagues who have seen it in their patients. Dr. David Okonkwo: I think it is important to remember that the plural of anecdote is not data. So what you are referring to
107 are Class 3 studies, and the only study with Class 1 evidence is Mike Diringer’s study out of St. Louis who led the neurocritical care fever reduction trial group. That is the only Class 1 evidence where this was specifically investigated with the use of intervascular cooling catheters, and there was no difference in the occurrence of venous thromboembolism in the intervascular cooling group versus the standard fever reduction group. Dr. Ard Struijs: The second question I have to you is that on one of your slides from the 24 TBI patients, you showed the x-ray of the chest. It was ventilated and prone in supine position and also nitric oxide was added to the treatment. Was the nitric oxide added for the ventilation problem? Mary Kay Bader: Yes, we have a pulmonary intensivist who manages a population of pulmonary hypertension patients and works with nitric oxide a lot. The patient’s PaO2 was in the 40s and his PbtO2 was drastically low. They had proned him for several days. They had tried every strategy there was available. They put him on nitric oxide for 14 days. When they called me about it, it was like, you have to be kidding me. I’d never heard of putting it into that population, but it was the last ditch effort. It did help him tremendously, and we could see the changes in the brain oxygen levels as we titrated the nitric oxide. It was pretty amazing. But I know there is no large study that has shown that it makes a difference in ARDS. Dr. Ard Struijs: The last question I have is for Colonel Rocco. You mentioned fever, but fever can be due to infection, to the severity of the brain trauma, to the inflammatory response. Is there any difference you can make if fever is a bad prognostic? For example, with spreading depression, is there more reason if you’ve got an infection? You’ve got no spreading depression, but that is really due to severe brain trauma that you get severe spreading depression. Do you know of any relationship between the reason for the fever and the effects on the brain injury? Dr. Rocco Armonda: It was fever independent of infection. Fever independent of infection is associated with poor outcome. In 2009, Todd looked at this very same entity and designed a study to look at whether preventing fever improves outcomes. He came up with this theoretical discussion that you would, in SAH patients, have to study 4,500 patients per group to identify that. What we do now is we say okay, with our current technology do we have the ability to control for fever? What do we have now in 2012 that we didn’t have before that we can have strategies to control fever? How can we apply this technology to prevent fever? Then at the same time, we have to be vigilant about the fact that we are not masking infections. Is there a change in the white count? Is there a change in the cooling temperature of your device that is trying to overcome temperature elevations to show evidence of infection? Are there other parameters that indicate a possible infection? But to answer your first question, fever independent of infection is associated with poor outcome and spreading depression. Number two is that you can’t really perform the study with that volume of patients. It just will not work in terms of coming up with the evidence-based Class 1 data.
108 Dr. Dalton Dietrich: I would just add that if you go back to the 1980s data with microdialysis and cortical spreading depression, the release of glutamate and potassium was all so very temperature sensitive. So it makes a lot of sense now that a secondary hyperthermic insult could actually aggravate neurochemical responses and promote repetitive episodes of cortical spreading depression. So again, as we already talked about, it appears that multiple concepts are coming together based on some older preclinical data and new clinical data. Dr. Greg Zorman: This is for any of the panelists. I know Colonel Armonda has published about this, but in the category of severe TBI patients, have you had any experience of vascular manipulation in that group of patients that developed vasospasm secondary to contusion to brain injury? Dr. Rocco Armonda: We certainly have. Our mechanisms might be different from what you see in typical civilian blunt trauma. If you have a younger patient who is not responding to therapies and who in fact has a large area of contused brain, we have seen in that patient population even with blunt trauma not related to blast associated superclinoid internal carotid artery cerebral vasospasm that we’ve treated with angioplasty and arterial Nicardipine. Dr. David Okonkwo: I think that vasospasm is a vastly underappreciated secondary injury mechanism in severe TBI. Key References from Panel Participants Armonda RA, Bell RS, Vo AH, Ling G, DeGraba TJ, Crandall B, Ecklund J, Campbell WW. Wartime traumatic cerebral vasospasm: recent review of combat casualties. Neurosurgery 2006;59:1215–1225; discussion 1225. Armonda RA, Thomas JE, Rosenwasser RH. Early and aggressive treatment of medically intractable cerebral vasospasm with pentobarbital coma, cerebral angioplasty and ICP reduction. Neurosurg Focus 1998;5:e7. Bader MK, Neal B, Johnson L, Pyle K, Brewer J, Luna M, Stalcup C, Whittaker M, Ritter M. Rescue me: saving the vulnerable non-ICU patient population. Jt Comm J Qual Patient Saf 2009;35:199–205. Bader MK, Rovzar M, Baumgartner L, Winokur R, Cline J, Schiffman G. Keeping cool: a case for hypothermia after car-
EXPERT PANEL DISCUSSION diopulmonary resuscitation. Am J Crit Care 2007;16:636, 632– 635. Bell RS, Ecker RD, Severson MA 3rd, Wanebo JE, Crandall B, Armonda RA. The evolution of the treatment of traumatic cerebrovascular injury during wartime. Neurosurg Focus 2010;28:E5. Clifton GL, Coffey CS, Fourwinds S, Zygun D, Valadka A, Smith KR Jr, Frisby ML, Bucholz RD, Wilde EA, Levin HS, Okonkwo DO. Early induction of hypothermia for evacuated intracranial hematomas: a post hoc analysis of two clinical trials. J Neurosurg 2012 Jul 27. (Epub ahead of print). Clifton GL, Valadka A, Zygun D, Coffey CS, Drever P, Fourwinds S, Janis LS, Wilde E, Taylor P, Harshman K, Conley A, 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. Ecker RD, Mulligan LP, Dirks M, Bell RS, Severson MA, Howard RS, Armonda RA. Outcomes of 33 patients from the wars in Iraq and Afghanistan undergoing bilateral or bicompartmental craniectomy. J Neurosurg 2011;115:124–129. 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. Hartings JA, Watanabe T, Bullock MR, Okonkwo DO, Fabricius M, Woitzik J, Dreier JP, Puccio A, Shutter LA, Pahl C, Strong AJ; Co-Operative Study on Brain Injury Depolarizations. Spreading depolarizations have prolonged direct current shifts and are associated with poor outcome in brain trauma. Brain 2011;134:1529–1540. Hertle DN, Dreier JP, Woitzik J, Hartings JA, Bullock R, Okonkwo DO, Shutter LA, Vidgeon S, Strong AJ, Kowoll C, Dohmen C, Diedler J, Veltkamp R, Bruckner T, Unterberg AW, Sakowitz OW; for the Cooperative Study of Brain Injury Depolarizations (COSBID). Effect of analgesics and sedatives on the occurrence of spreading depolarizations accompanying acute brain injury. Brain 2012;135:2390–2398. Presciutti M, Bader MK, Hepburn M. Shivering management during therapeutic temperature modulation: nurses’ perspective. Crit Care Nurse 2012;32:33–42.
Expert Panel Discussions
Temperature Management in Neurological and Neurosurgical Intensive Care Unit Moderator: W. Dalton Dietrich, Ph.D.1 Participants: David O. Okonkwo, M.D., Ph.D.,2 Mary Kay Bader, R.N., M.S.N.,3 and Colonel Rocco Armonda, M.D.4
A major use of therapeutic hypothermia and temperature management occurs within the neuroscience ICU units where state-of-theart imaging and monitoring equipment are used to evaluate injury mechanisms and targets for therapeutic interventions. Previous experimental and clinical studies have demonstrated the beneficial effects of mild hypothermia in terms of protecting the injured brain from secondary insults, as well as the importance of limiting periods of reactive hyperthermia in the post-injury setting. A series of stateof-the-art lectures presented at the 2nd Annual Therapeutic Hypothermia and Temperature Management Meeting in Miami brought together experts in the field of temperature management in neurological and neurosurgical intensive care units (ICU). Dr. David Okonkwo, Director of the Neurotrauma Program at the University of Pittsburgh discussed controversies in the use of hypothermia targeting traumatic brain injury (TBI). Dr. Okonkwo emphasized the recent results from the NABISH hypothermia trials as well as new diagnostic targets that could be used to guide temperature management strategies. Recently, the renewed interest in cortical spreading depolarization as a secondary insult has been emphasized. Importantly, these repetitive ionic insults in the postinjured brain appear to be extremely temperature sensitive and a potentially significant secondary insult that needs to be monitored and prevented. Mary Kay Bader, an Intensive Care Nurse and spokesperson for the use of temperature management strategies in various patient populations, presented an important presentation on nursing support in the ICU for hypothermic therapy. Mrs. Bader emphasized the need for established protocols to be followed in terms of the use of hypothermia and other critical care procedures that must be implemented to maximally improve outcome in various patient populations. The point that ‘‘champions’’ need to be identified to promote and lead the use of hypothermia in various hospital situations was emphasized, as well as the importance of experienced critical care nurses at the bedside to continuously monitor patient status. Dr. Colonel Rocco Armonda, Director of the Cerebrovascular Surgery and Interventional Neuroradiology at the Walter Reed Hospital, presented an important topic regarding cooling and subarachnoid hemorrhage (SAH) and vasospasm. Vasospasm is a potential consequence of SAH or trauma that can
lead to high morbidity and mortality. Recent studies have investigated underlying pathophysiological mechanisms for the generation of vasospasm as well as the effects of induced hypothermia or periods of hyperthermia on the frequency of vasospasm. New monitoring approaches are required to evaluate the hemodynamic status of tissue including the use of microdialysis to gauge degrees of vasospasm-induced ischemia. It is clear from these studies that the brain can have a critical influence on many biochemical and molecular mechanisms of injury that need to be monitored and evaluated at the bedside. Dr. Carmelo Graffagnino: A question regarding cortical spreading depression to the whole panel. Do you think that the spreading depression is a marker of ischemic severity and that hypothermia is protecting the injured brain, or do you think that there is also pathology created by the spreading depression and activation of the ischemic cortex and that hypothermia is tuning down the electrical function of the brain sufficiently to protect it from the damage produced by the spreading depression? What I worry about is whether electrophysiological alternating drugs like antiepileptics block spreading depression, and if so, do you think this would be a compounding effect in your clinical trials? Dr. David Okonkwo: So, those are great questions, and I’ll take the first step. With respect to the first point you brought up, from my perspective, it’s both. Spreading depression is both a reflection of the severity of the injury and a contribution to ongoing and worsening pathology. I say that for several reasons. If you remember one of Dr. Armonda’s slides, showing the relationship of fever to the occurrence of spreading depression, there is no reason for spreading depression to induce a fever. So, it should be in response to fever, setting the conditions for the increased potential for spreading depression to develop. But, by the same token, we also know, from Dr. Tony Strong’s perspective of spreading depression being a brain tsunami, that it leaves behind additional damage. This is over and above the fact that the more severely
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Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, Florida. Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania. 3 Mission Hospital, Mission Viejo, California. 4 National Navy MEDCEN and Walter Reed Army MEDCEN, Bethesda, Maryland. 2
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EXPERT PANEL DISCUSSION injured you are, the more likely you are to develop spreading depression. The second question about the use of antiepileptics, we have not found an influence of the use of either Dilantin or Keppra on the overall incidence of spreading depression in the TBI population. However, I do not routinely take care of aneurysm patients anymore. Are you still using prophylactic antiepileptic therapy? Dr. Rocco Armonda: We actually avoid the use of Dilantin now because Dilantin actually has a worsening effect in most cases. We have gone to Keppra in selected patients. The patients that seem to be the highest risk for spreading depression scenarios in SAH are usually the poorer grade patients, higher blood burden. Patients who are elderly also have some higher incidence of seizures as well. Spreading depression is different from what we see in terms of postoperative or subarachnoid seizures. It’s a different entity. We think that perhaps spreading depression may explain this entity of microvascular spasm that we don’t necessarily see angiographically that may in fact lead to more of these encephalopathic global changes that are ongoing. It’s very hard to say if it is associative or causative for the patient’s deficit. Is it something that is just going to be associated with significant burden of injury or is it causing the burden of injury. Certainly, we see worse outcomes with those patients who have a higher incidence of spreading depression. More so than just their SAH grade. Dr. David Okonkwo: Our German collaborators with the COSBID group obtained absolute mountains of data from all of the centers looking at what had happened to these patients in the ICU that was not directed at the spreading depression. Assessing the use of antiepileptics, sedatives, and narcotics, they tried to map the use of all the pharmacologic agents. This is not a trivial exercise. And the only drug that had an influence on spreading depression was Ketamine. So now we understand two things that influence spreading depression: temperature and Ketamine. But none of the others had been shown to have a significant correlation with the incidence of spreading depression. Dr. Hans Friberg: I’m also thrilled and intrigued by this discussion about spreading depression. My background is a laboratory setting, and we induce spreading depression all the time—that’s no problem. I was not aware of the fact that this is maybe an important issue in the adult brain. Would this be important regardless of whether it’s a focal ischemic or a global brain ischemic insult, for example after cardiac arrest? The main issue, how do we monitor it? You already replied that there are big problems treating it, but do we monitor it with continuous EEG, or how do we do it? Dr. David Okonkwo: I wish Jed Hartings, Tony Strong, or other real experts in spreading depression could participate in answering these great questions. Here’s the thing. The problem in 2012 is the only way to monitor this is to place a strip electrode on the surface of the brain. Therefore we are restricted to patients who are participating in research protocols wherein a craniotomy is being performed for some other reason. We are not in a position to deploy this in a routine clinical scenario yet. Now, some investigators are working very hard to come up with a way to use surface electrodes to
105 actually capture spreading depression events. At a recent meeting I attended, pilot data were shown that were highly encouraging. But we are not quite sure whether we can actually capture these events in the absence of invasive monitoring placed on the surface of the brain. That’s number one. Number two is whether this is a focal or a global event. Almost by definition, you have to look at spreading depression as a focal event. That’s because it happens in specific scenarios. When we are assessing CSD in the setting of brain injury, we are actually intentionally placing the electrode next to what looks like a contused brain because we know that we are more likely to capture the events in a penumbral brain region adjacent to contused brain. The same concept is appropriate in stroke where you are targeting the penumbra because we know that that is where we are more likely to find these transient events occurring as opposed to somewhere remote in the brain away from the primary focus of ischemic injury. Is that the answer to your question? Dr. Dalton Dietrich: Yes, I think so. Dr. Rainer Kollmar: I have a question about SAH. We recently started to cool these patients with a high Fisher grade, and the objective for this was that they had an elevated intracrancial pressure (ICP). The question is whether the cooling treatment was affecting the severity of vasospasm. We are facing the problem of how to really measure this vasospasm if the patients are cooled. How are you doing your titration if for example, you rewarm with, say, plateau phases where these patients have vasospasm? What is your objective? Do you always transfer these patients to the angiography laboratory or are you using ultrasound? Dr. Rocco Armonda: We start with transcranial Dopplers (TCDs), and in the poorest grade patients we also have ongoing brain tissue oxygen monitoring. So you have brain tissue oxygen (PbtO2) and TCDs. The problem is that the TCDs are only useful if in fact they are high or if there is a significant change. So then we have patients that we may not be picking up conducting vessel vasospasm. So the third entity, which I’m very excited about that I think may be even more helpful, is continuous EEG. We have a select group of patients on whom we started continuous EEG but were unable to see evidence of distal ischemia. The problem is that, in some of these patients, you’ll do an angiogram, and they have fairly severe vasospasm without a big change in their PbtO2 because their leptomeningial circulation has basically compensated for that hemodynamic state. In other patients, you see no conducting vessel vasospasm of the superclinoid carotid, or middle cerebral artery (MCA). However, the microcirculation is in spasm or is being stressed, and they’ll have a drop in the PbtO2 with normal lung function, and we can’t explain it based on the TCDs. So I think it is very difficult depending upon the type of area of the circulation that is being affected: proximal, distal, or diffuse combine vasospasm, which by that point becomes more obvious and less responsive to treatment. So my advice is that if in fact you are dealing with somebody with whom you are using hypothermia and you are using it for ICP protection, certainly your ICP is going to give you an indicator of the rewarming period. Rewarming is usually where it is most dangerous for vasospasm and in stroke because there is poor perfusion to
106 hyperemia rebound. But if you titrate that to the PbtO2 or to TCD readings and continuous EEG, you will be less likely to be rewarming them in a period when they are in vasospasm. You have to individualize that patient’s rewarm schedule. In some patients where TCDs are unobtainable, you can basically have no indicator of vasospasm due to poor bone windows, but when you take them to angiography, they have severe spasm. Mary Kay Bader: Our approach is similar to Rocco’s. Our neurosurgeons will monitor CT angiograms (CTAs) to look at the vessels for vasospasm as they make decisions on whether it is time to start rewarming. We do not obtain CTAs daily but monitor them periodically to see if there is diffuse spasm. Dr. Rocco Armonda: CT perfusion is labor intensive, requiring transport and a large contrast load. So it is very difficult in terms of the timing. You’d like to have the ideal monitor. Maybe microdialysis would be the answer in terms of seeing whether these patients are in a metabolic crisis. We just don’t have a good enough monitor to say truly if a patient is in spasm or not. Dr. Karen Porth: Quantitative EEG? Dr. Rocco Armonda: Absolutely, yes, quantitative EEG—that you could track. So if you are tracking a patient before you put them into hypothermia and then during the cooling period, you can then follow them over an extended period. Dr. Karen Porth: I’m a vascular neurologist, and I was going to comment about quantitative EEG and doing that continuously. The other thing I was going to comment about is that Ketamine is my new drug of choice for status because for patients with vasospasm or who have SAH, and it’s really nice in vasospasm patients because it doesn’t cause hypotension. So that was interesting what you were saying about Ketamine not having an effect on cortical spreading depression. Dr. Rocco Armonda: Isn’t that a paradox? When you think about it, we all were brought up to think of Ketamine as lowering your seizure threshold, right? It has a reverse effect perhaps on spreading depression. Dr. Ross Bullock: We have an ongoing debate in our ICU with some of the intensivists about the fact that hypothermia may be harmful in terms of worsening pneumonia. Everybody knows that there are theoretical lab data that it suppresses immune function, and they cite to us some literature that shows that it has been shown to worsen pneumonia. ICU nurses are closest to that kind of information, so my question primarily for Mary Kay is what do you think about that debate? Mary Kay Bader: I think there is validity that they are at increased risk for ventilator-associated pneumonia and for Acute Respiratory Distress Syndrome (ARDS). Sometimes IV fluid intake increases insidiously 2 liters positive per day and the trend continues for 5 days. Suddenly the patient is 10 liters positive at 5 days and the team has not realized it. There are complications because of this trend. We focus in on aggressive patient turning, aggressive head of the bed up as much as
EXPERT PANEL DISCUSSION possible, percussion; we’ve even proned patients who are hypothermic if their lungs are getting worse. So it really takes the ICU nurse, the intensivist, and the respiratory therapist to all work together, but it is a serious problem. Sometimes you’ll hear nurses say that the patient’s ICP is just so high, I can’t turn them. Well, no, you have to turn them. Because if you lay that patient in the bed and don’t do anything, I guarantee you they are going to have a pulmonary problem. So it is about being very aggressive. Dr. Patrick Kochanek: Dave, I really enjoyed your lecture. I was wondering about a topic that is kind of a different angle on the findings that you have presented. You know there is a considerable body of data that says that hypothermia attenuates axonal injury in experimental models of TBI, yet the Clifton study showed the worsening of outcome in the patients with, if you want to call it, a diffuse axonal injury (DAI) type of profile. So I am interested in your thoughts on why you think hypothermia is actually deleterious rather than beneficial and the clinical angle on that. Dr. David Okonkwo: There is an important point about the NABISH studies that I don’t think gets discussed enough. This is one of the things that we appreciated as we were putting the papers together. Those studies were designed for hypothermia to be a primary neuroprotectant. This was a guess, just like the magnesium TBI study was a guess that turned out to be a very wrong guess of the dose of magnesium and it led to higher mortality. So there was a guess of the dose and time of hypothermia in this cooling study. I don’t think that the time of hypothermia in the NABISH studies of 48 hours is sufficient to take into account the pathology of the evolution of axonal injury that we’ve learned from John Povlishock over the years takes longer than that in the human to finish playing itself out. As we know, the Chinese study of hypothermia maintained hypothermia for much longer. If and when we do this third iteration of a multicenter hypothermia trial, duration of cooling will still be one of the critical remaining features for us to work. What will be our triggers to initiate rewarming as opposed to just a strict 48 hours and is it time to rewarm? We haven’t actually come to the right conclusion about that yet. But I think the dose and the time were wrong to target that patient population. Dr. Neeraj Badjatia: Just going back to the discussion about vasospasm and how to monitor for it. At Columbia, we’ve been doing what we call a neuromonitoring bundle where, in addition to Lycox and microdialysis, we place a CBF probe, a depth EEG, and surface EEG as well as a drug bulb just to get at this question of how can you better target and monitor an organ of interest, which is the brain. I’ve got to say, as much data as we’ve collected and we’ve learned, it’s very complicated obviously. What we think is that microdialysis measurements do help, but they doesn’t help by themselves. PbtO2 helps, but as you know it doesn’t help by itself. Surface EEG, while we had a lot of hope that it would be a vasospasm monitor, the reality is it’s a great spasm monitor in patients who aren’t moderately or deeply sedated. I think what we are talking about is that we’ve got these great physiological tools, but now we are actually at the point where we need to think about how to analyze and interpret the data in a meaningful way.
EXPERT PANEL DISCUSSION Dr. David Okonkwo: In real time? Dr. Neeraj Badjatia: Yes, in real time. That is exactly the case, for example, with the depth EEG monitor, I think, I was told about half a million minutes worth of EEG data that had to be coded in a way that you could analyze it. Our informatics department has just become like a Ph.D. project for a couple of graduate students now to analyze these data. So it is becoming an enormous amount of data, an enormous amount of analysis. It’s a whole different field, in a sense, this use of informatics to try and understand the readings. But getting back to the first question about how do we track in hypothermic patient spasms, we use all of the above that was mentioned. We use CT perfusion, we use our changes in alpha–delta ratios if we can watch those. I think microdialysis is really the best tissue marker that we have of metabolism during cooling at this point because we actually see significant changes during shivering that sometimes trigger us to look at the patient. Kind of the reverse of what you think about, but we see the changes on the monitors first. Dr. David Okonkwo: Where do you place the microdialysis probe? Dr. Neeraj Badjatia: In SAH patients, it tends to be on the side where there is more blood, if there is more blood on one side or the other. There is some talk about doing the reading on both sides, but we are now talking about already two to three burr holes on one side. At a certain point, you reach some limitation. So, I think microdialysis is really going to help us, although we’re several years away from really fully understanding how it is going to help us. But we are learning a lot at this point, and certainly with hypothermia, I think it is one of the ways for us to track spasms. In fact, we are doing it in our cardiac arrest patients too: to track when to rewarm and how long to cool somebody. Mary Kay’s point about fluid management is absolutely right. In our prospective data set that we have, we found that fluid management or mismanagement was an independent driver of morbidity to mortality. We are putting those data together right now. So I think this is an important aspect of hypothermia management. Dr. Ard Struijs: I’ve got three short questions. The first to Mary Kay. You mentioned on your slides that there is the high risk for venous embolism by cooling intervascularly. I’ve been doing it for more than 10 years, and I didn’t see this problem. Do you have more data about this? Mary Kay Bader: I don’t have any personal data because we do not use that system, but I have colleagues who have used intervascular systems and have spoken of the incidence of deep vein thrombosis (DVT) or venous thromboembolism. There are a few studies out there that have shown that it is a question of surveillance, I think. Do we look for it? Are we routinely screening our patients for that? So if you don’t see it, if you are not monitoring or screening for it, is it not happening? It is one of the risks that have been identified in the literature. There are risks to each system. But, I have had colleagues who have seen it in their patients. Dr. David Okonkwo: I think it is important to remember that the plural of anecdote is not data. So what you are referring to
107 are Class 3 studies, and the only study with Class 1 evidence is Mike Diringer’s study out of St. Louis who led the neurocritical care fever reduction trial group. That is the only Class 1 evidence where this was specifically investigated with the use of intervascular cooling catheters, and there was no difference in the occurrence of venous thromboembolism in the intervascular cooling group versus the standard fever reduction group. Dr. Ard Struijs: The second question I have to you is that on one of your slides from the 24 TBI patients, you showed the x-ray of the chest. It was ventilated and prone in supine position and also nitric oxide was added to the treatment. Was the nitric oxide added for the ventilation problem? Mary Kay Bader: Yes, we have a pulmonary intensivist who manages a population of pulmonary hypertension patients and works with nitric oxide a lot. The patient’s PaO2 was in the 40s and his PbtO2 was drastically low. They had proned him for several days. They had tried every strategy there was available. They put him on nitric oxide for 14 days. When they called me about it, it was like, you have to be kidding me. I’d never heard of putting it into that population, but it was the last ditch effort. It did help him tremendously, and we could see the changes in the brain oxygen levels as we titrated the nitric oxide. It was pretty amazing. But I know there is no large study that has shown that it makes a difference in ARDS. Dr. Ard Struijs: The last question I have is for Colonel Rocco. You mentioned fever, but fever can be due to infection, to the severity of the brain trauma, to the inflammatory response. Is there any difference you can make if fever is a bad prognostic? For example, with spreading depression, is there more reason if you’ve got an infection? You’ve got no spreading depression, but that is really due to severe brain trauma that you get severe spreading depression. Do you know of any relationship between the reason for the fever and the effects on the brain injury? Dr. Rocco Armonda: It was fever independent of infection. Fever independent of infection is associated with poor outcome. In 2009, Todd looked at this very same entity and designed a study to look at whether preventing fever improves outcomes. He came up with this theoretical discussion that you would, in SAH patients, have to study 4,500 patients per group to identify that. What we do now is we say okay, with our current technology do we have the ability to control for fever? What do we have now in 2012 that we didn’t have before that we can have strategies to control fever? How can we apply this technology to prevent fever? Then at the same time, we have to be vigilant about the fact that we are not masking infections. Is there a change in the white count? Is there a change in the cooling temperature of your device that is trying to overcome temperature elevations to show evidence of infection? Are there other parameters that indicate a possible infection? But to answer your first question, fever independent of infection is associated with poor outcome and spreading depression. Number two is that you can’t really perform the study with that volume of patients. It just will not work in terms of coming up with the evidence-based Class 1 data.
108 Dr. Dalton Dietrich: I would just add that if you go back to the 1980s data with microdialysis and cortical spreading depression, the release of glutamate and potassium was all so very temperature sensitive. So it makes a lot of sense now that a secondary hyperthermic insult could actually aggravate neurochemical responses and promote repetitive episodes of cortical spreading depression. So again, as we already talked about, it appears that multiple concepts are coming together based on some older preclinical data and new clinical data. Dr. Greg Zorman: This is for any of the panelists. I know Colonel Armonda has published about this, but in the category of severe TBI patients, have you had any experience of vascular manipulation in that group of patients that developed vasospasm secondary to contusion to brain injury? Dr. Rocco Armonda: We certainly have. Our mechanisms might be different from what you see in typical civilian blunt trauma. If you have a younger patient who is not responding to therapies and who in fact has a large area of contused brain, we have seen in that patient population even with blunt trauma not related to blast associated superclinoid internal carotid artery cerebral vasospasm that we’ve treated with angioplasty and arterial Nicardipine. Dr. David Okonkwo: I think that vasospasm is a vastly underappreciated secondary injury mechanism in severe TBI. Key References from Panel Participants Armonda RA, Bell RS, Vo AH, Ling G, DeGraba TJ, Crandall B, Ecklund J, Campbell WW. Wartime traumatic cerebral vasospasm: recent review of combat casualties. Neurosurgery 2006;59:1215–1225; discussion 1225. Armonda RA, Thomas JE, Rosenwasser RH. Early and aggressive treatment of medically intractable cerebral vasospasm with pentobarbital coma, cerebral angioplasty and ICP reduction. Neurosurg Focus 1998;5:e7. Bader MK, Neal B, Johnson L, Pyle K, Brewer J, Luna M, Stalcup C, Whittaker M, Ritter M. Rescue me: saving the vulnerable non-ICU patient population. Jt Comm J Qual Patient Saf 2009;35:199–205. Bader MK, Rovzar M, Baumgartner L, Winokur R, Cline J, Schiffman G. Keeping cool: a case for hypothermia after car-
EXPERT PANEL DISCUSSION diopulmonary resuscitation. Am J Crit Care 2007;16:636, 632– 635. Bell RS, Ecker RD, Severson MA 3rd, Wanebo JE, Crandall B, Armonda RA. The evolution of the treatment of traumatic cerebrovascular injury during wartime. Neurosurg Focus 2010;28:E5. Clifton GL, Coffey CS, Fourwinds S, Zygun D, Valadka A, Smith KR Jr, Frisby ML, Bucholz RD, Wilde EA, Levin HS, Okonkwo DO. Early induction of hypothermia for evacuated intracranial hematomas: a post hoc analysis of two clinical trials. J Neurosurg 2012 Jul 27. (Epub ahead of print). Clifton GL, Valadka A, Zygun D, Coffey CS, Drever P, Fourwinds S, Janis LS, Wilde E, Taylor P, Harshman K, Conley A, 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. Ecker RD, Mulligan LP, Dirks M, Bell RS, Severson MA, Howard RS, Armonda RA. Outcomes of 33 patients from the wars in Iraq and Afghanistan undergoing bilateral or bicompartmental craniectomy. J Neurosurg 2011;115:124–129. 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. Hartings JA, Watanabe T, Bullock MR, Okonkwo DO, Fabricius M, Woitzik J, Dreier JP, Puccio A, Shutter LA, Pahl C, Strong AJ; Co-Operative Study on Brain Injury Depolarizations. Spreading depolarizations have prolonged direct current shifts and are associated with poor outcome in brain trauma. Brain 2011;134:1529–1540. Hertle DN, Dreier JP, Woitzik J, Hartings JA, Bullock R, Okonkwo DO, Shutter LA, Vidgeon S, Strong AJ, Kowoll C, Dohmen C, Diedler J, Veltkamp R, Bruckner T, Unterberg AW, Sakowitz OW; for the Cooperative Study of Brain Injury Depolarizations (COSBID). Effect of analgesics and sedatives on the occurrence of spreading depolarizations accompanying acute brain injury. Brain 2012;135:2390–2398. Presciutti M, Bader MK, Hepburn M. Shivering management during therapeutic temperature modulation: nurses’ perspective. Crit Care Nurse 2012;32:33–42.
