THERAPEUTIC HYPOTHERMIA AND TEMPERATURE MANAGEMENT Volume 2, Number 4, 2012 ª Mary Ann Liebert, Inc. DOI: 10.1089/ther.2012.1519
Cooling Strategies Targeting Trauma Moderator: W. Dalton Dietrich, Ph.D.1 Participants: John T. Povlishock, Ph.D.,2 Guy Clifton, M.D.,3 M. Ross Bullock, M.D., Ph.D.,1 and Michael Y. Wang, M.D., Ph.D.1
Therapeutic hypothermia and temperature management has now been utilized in a variety of clinical situations following neurotrauma. Single as well as multicenter trials have been conducted to evaluate whether therapeutic hypothermia is beneficial in patients following severe traumatic brain injury (TBI). Although early studies indicated that cooling was effective in reducing mortality and improving functional outcome in TBI patients, subsequent multicenter trials including the National Acute Brain Injury Study: Hypothermia (NABIS-H) trials failed to show efficacy. Various publications have provided insight into the complexity of TBI and potential reasons why early cooling was ineffective in these multicenter trials. Recently, therapeutic hypothermia has also been initiated in patients with severe cervical spinal cord injury. Prolonged periods of systemic hypothermia appear in preliminary single institutions programs to be safe, and may improve functional outcome at 1 year. A series of state-of-the-art lectures presented at the 2012 Therapeutic Hypothermia and Temperature Management meeting in Miami brought together experts in the field of brain and spinal cord injury to discuss the use of therapeutic hypothermia in these patient populations. Dr. John Povlishock, Professor and Chair, Department of Anatomy and Neurobiology at the Virginia Commonwealth University, discussed treating diffuse axonal injury with hypothermia and combination approaches. Dr. Povlishock and colleagues have demonstrated that early cooling in models of TBI have a beneficial effect on reducing overall axonal pathology, a hallmark of TBI. More recently, combination approaches where hypothermia is coupled with specific neuroprotective compounds may produce a synergistic effect on outcome were also discussed. Dr. Guy Clifton, Professor of Neurosurgery at the University of Texas, reviewed his recent provocative data regarding subgroup analysis of the various NABIS-H trials. Dr. Clifton and associates have determined in a limited number of subjects that early hypothermia may be most protective in patients undergoing decompression surgery in contrast to diffuse axonal injury. Concepts regarding therapeutic window of cooling protocols depending on what mechanisms were being targeted were emphasized in this discussion. Dr. Ross Bullock, Director of Clinical Neurotrauma in the Department of Neurological Surgery at the University of Miami, emphasized reperfusion injury as a target for early cooling after TBI. Dr. Bullock and colleagues have recently attempted to test Dr. Clifton’s hypothesis regarding whether an animal model of subdural hematoma with evacuation would benefit from a
cooling strategy initiated prior to the decompression surgery. Results seem to support that hypothesis. Finally, Dr. Michael Wang, Professor of Neurological Surgery at the University of Miami, summarized recent progress in spinal cord injury hypothermia trials. Dr. Wang and colleagues have conducted an IRB-approved study where approximately 45 patients with severe cervical spinal cord injury have undergone whole body cooling for 48 hours followed by a slow rewarming phase. Published data indicate safety as well as some degree of efficacy at 1 year. Thus it is clear from these experimental and clinical investigations that therapeutic hypothermia certainly has a place in targeting neurotrauma with a need for further laboratory and clinical investigations to continue to move this experimental therapy forward. Dr. Guy Clifton: In the Japanese ‘‘B-HYPO’’ trial, was the outcome for the evacuated mass lesion group the primary objective, or was that also a post-hoc subgroup analysis, as with the NABIS-H trials? Dr. Ross Bullock: The latter. Exactly as with the NABIS-H trial. As far as I know, Dr. Yokobori is here. He may know the Japanese literature better than me. Any comments Dr. Yokobori? Dr. Shoji Yokobori: The hypothermia study has not yet been published—only personal communication of early data. I hope we can have the publication out by next year. Dr. Guy Clifton: Were the cooling times short in that study— in the Japanese B-HYPO study? Do you know? Dr. Shoji Yokobori: I think 48 to 72 hours was the cooling time. Dr. David Erlinge: Question to Dr. Wang—Why just ASIA A patients in your study? Also, we know from the spinal cord injury model systems that the first reliable ASIA score isn’t for 72 hours. Dr. Michael Wang: That’s a great question, David. The ASIA A was made I think initially when this data collection process
1
Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, Florida. Department of Anatomy and Neurobiology, Medical College of Virginia/Virginia Commonwealth University, Richmond, Virginia. Department of Neurosurgery, University of Texas Medical School at Houston, Houston, Texas.
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was first started 5 years ago, we weren’t really sure that we could prove safety. I think we’ve gotten to the point where we feel that it is a safe intervention. Thus, in our RO1 submission, we are looking at both ASIA As and Bs for that very reason. Of course, if you enroll less severely injured patients, including ASIA B, C, and D, the heterogeneity of the recovery pattern starts to become a concern. Then we start to look at a sample number to power our study, and it is going to be just simply too big and undoable. In our trial, we are looking at A and B because that will mean those who have no movement below the lesion. But great question.
ischemia/reperfusion injury, which you think you may have had a benefit for in NABIS-H II or when you are trying to treat brain edema or both. This is an important consideration in reference to the timing of hypothermia and duration of hypothermia. I wondered if you and the other members of the panel would comment on whether, in a patient with ongoing brain edema, we might require a different strategy and a different duration of therapy than in patients where we are treating pure ischemia/reperfusion, Although this may rarely occur, but as you made the point, sometimes it is the case in TBI.
Question: How frequently are the patients surgically fixed?
Dr. Guy Clifton: That is a great point. I was asked by Dalton to do a review on brain injury trials in hypothermia. In the distinction I made in that review, I discussed these different mechanisms of protection with hypothermia. I separated them out into those that were purely neuroprotective and those that were more purely for treatment of intracranial pressure (ICP), and then a lot of them merged the two. I think this is the reason for the discrepancies that we are seeing in the results. So, what would you do for ICP treatment? Start later and go longer. For neuroprotection, start early and maybe for not so long. We solved the hypotension problem that, as you pointed out from the first, was a problem in NABIS-H I by fluid expansion. But I think the price we paid was more ICP problems. In retrospect, I would have changed the trial by individualizing the period of rewarming to take account of ICP. So I think there are lessons to be learned. I hope future trial designs really make the distinction of which mechanism they are testing or if they are testing both.
Dr. Michael Wang: 100% of our patients are getting decompression surgery. Question: How many days after? Dr. Michael Wang: Almost all the patients are getting decompressed within a day. Question: One day? Dr. Michael Wang: Less than 12 hours in most cases. But definitely within 24 hours. So when you look at the 42% improvement rate, some people are going to look at that and say, well, how do you know this isn’t from your early decompression surgery? So that’s a very good point. These patients are getting early and optimized care as well. Question: My other question regarding your series is whether anyone was extubated during the cooling period? All of them were intubated? Response: No, in fact many of our patients are not intubated. Question: During the period of hypothermia?
Question: I’ve got a question for Dr. Wang. You showed a slide that showed you have a very high rate of atelectasis. I was surprised. But then you told me most patients were not ventilated. So now I understand why they have atelectasis. But if you are cooling them, and you have a risk of pneumonia, and you are not aware atelectasis causes pneumonia, too, why don’t you use continuous positive airway pressure (CPAP) to prevent pneumonia, too?
Dr. Michael Wang: That’s correct. Question: OK. The other question is, after the hypothermia, do you keep the patients normothermic to avoid prolonging of the fever? Dr. Michael Wang: Yes, we do that. We warm them for a 24hour period, and we try to get the cooling catheters out. Question: Is there a normotherapy protocol after the patient has had the catheter removed? Dr. Michael Wang: Are you asking whether we do something to maintain normothermia? Question: Exactly. Dr. Michael Wang: Yes, absolutely. But not necessarily with invasive technique. Dr. Kees Polderman: Dr. Clifton, I enjoyed your talk. The field now has more than 20 years’ experience in TBI trials. I always like to distinguish whether we are trying to treat
Dr. Michael Wang: I think that’s a great point. I think that how you define atelectasis, right, it can be difficult. So our definition is relatively broad. I think that you can get into this point of where you are chasing your tail in terms of categorizing them as having had an adverse event. For example, CPAP has its own particular problems with these patients, as well, in terms of getting them ventilated properly. However, I think if you compare our results with our historical cohort, we are not seeing higher rates of the complications. That’s really the important point. If you look at a single center like ours, and you say, well, we had a 100% rate of atelectasis 6 years ago, as well, then we are not seeing higher rates of atelectasis. Dr. Dalton Dietrich: So Ross and Mike, since you are sitting together, let me ask you a question. Do you see similarities between traumatic brain injury and spinal cord injury in terms of this phenomenon of reperfusion injury that Guy has talked about? If we find out at the end of the day that it’s better to have the patient cooled when you decompress the brain after trauma, will it not also make sense in terms of spinal cord injury to have the patient cooled when you decompress?
164 Dr. Ross Bullock: The difference in the TBI situation is we have ICP to worry about, which we probably don’t have to worry about that in spinal cord injury. But there is the possibility that the swollen spinal cord might be filling that spinal canal and that this early surgery point may play out to be more important. You know, I think the point that Guy makes that ICP control is an extra benefit you get from hypothermia in severe TBI, that’s very true. Absolutely. I think that if one or other trial or if a TBI trial shows benefit with the hypothermia, the timing of decompression of the spinal cord will also be crucially important. Dr. Michael Wang: I agree with everything Ross said. I think the issue with the spinal cord is that we don’t understand the autoregulatory process in the spinal cord very well. I don’t think that it is quite that elegantly appreciated. It would make sense, right? It would make a lot of sense to take that sort of approach. I think that’s the direction we are moving, right? Dr. Dalton Dietrich: So when you decompress the cord, what’s the temperature of the spinal cord normally? Dr. Michael Wang: At University of Miami, it’s 33C. Dr. Guy Clifton: I was going to make a comment regarding diffuse injury. The puzzle is why there is such strong laboratory data on hypothermia protecting against axonal pathology. Dr. Povlishock showed that posttraumatic hypothermia significantly reduced indicators of DAI. However, we failed to demonstrate it clinically. This inconsistency may be due to the time window. I was thinking about this while John was talking. With hematomas, if this ends up proving out, we’ve been given a pass on the window because reperfusion doesn’t start until you get the clot out. You’ve got ischemia before that. So you’ve really been given a prolonged window. We knew in cortical contusion injury, just empirically in the laboratory, that after 90 minutes, hypothermia doesn’t work, at least in our models. I noticed that John was treating at about 15 minutes. I don’t think we could have cooled any faster than we did in NABIS-H II. Logistically, I don’t even think even with intravascular cooling catheters you could; I don’t know how you could get them in any faster. If in fact for diffuse injury, there is a very narrow window that we met with hematomas just because surgeries take place later, then the answer may ultimately be earlier cooling. But if technically you can’t do it, a strategy would be to combine the mitochondrial stabilizers like cyclosporine A with hypothermia in order to buy time. With diffusion injury, there may simply be a window issue that we’ve not been able to solve in a clinical setting. Dr. Dalton Dietrich: So ladies and gentlemen, how easy is it going to be to conduct a combination clinical trial where you have hypothermia plus a drug? Isn’t that going to be relatively difficult to put together? Dr. John Povlishock: Sure, it’s going to be difficult to get together. But again, if we have more enduring preclinical evidence, I think that’s what the NIH wants to see—that you could document a time frame that would be realistic in a human scenario. There would be interest to move forward, but there is also reluctance because each clinical trial that the
EXPERT PANEL DISCUSSION NIH funds costs about 15 million dollars, at least from the NINDS. So this is a very expensive enterprise. I think they want to see evidence of protection in higher-order animals. And I’m quietly confident it can be done. I want to say one thing to Dr. Wang. You discussed a very interesting history of steroids that was very instructive to this audience. When that study was rolled out, Mike Bracken was an epidemiologist who had championed their use. When that was presented to the neurosurgical community, there was really quite a bit of uproar in the audience. Because the reality is, when you looked at the data, those treated patients only had a very subtle change in sensory improvement. It wasn’t motor; it was only a very subtle sensory change. I think that shows you the fallacy of sometimes rushing too soon to treat. There was so much enthusiasm that maybe this treatment would work without the adequate preclinical and clinical data that they launched these multicenter trials. I think, in hypothermia and actually in other cases, we have more robust data. But we are being more careful now and not as reflexive in our response. Dr. Guy Clifton: I’ve got to say that I still remember before that paper was published, a fax showed up on my desk—with the abstract before anybody had ever reviewed the data. You were essentially told that you’re going to get sued if your patients don’t get this treatment. It was instantly adopted, and, as John said, there was a lot of hypertension. Dr. John Povlishock: Dr. Wang, you want to comment? Dr. Michael Wang: Well, we don’t want to reproduce history in that way, and so I think, on a spinal cord front, it is just a very emotional lightening rod, right? The Kevin Everett story where the NFL player received hypothermia after cervical spinal cord injury, I think, was our Miami foray into that. As we move forward, we need to establish a high level of evidence for this intervention, and we need to have good quality trials. The question is how do we fund that? And that’s really the issue here. I think everybody is motivated to do it. Dr. Ross Bullock: One point is that recently a European company came up with a more so-called brain-bioavailable adjunct of cyclosporine. The rumor on the street is that they have high levels of investor funding and that there is interest in trials in Europe. So that may be a way forward—a threearmed trial or placebo: the new cyclosporine A and hypothermia plus cyclosporine A. It’s some kind of a more interesting paradigm like that. Dr. John Povlishock: The drug doesn’t have immunosuppressant properties, so it doesn’t pose a risk to the patient, but it still protects mitochondria. Dr. Dalton Dietrich: David, any words of wisdom from a cardiologist in terms of what cooling strategies we are trying to do in CNS injury? Dr. David Erlinge: Regarding the discussion about reperfusion injury, I definitely think you should cool them before you decompress. It appears to be the right thing to do. Dr. Dalton Dietrich: Any other comments from the audience for our lecturers today? Well, thank you all for being here.
EXPERT PANEL DISCUSSION Thank you all for the presentations. Again, the audience participation was fantastic. Key References for Panel Participants Ahmad FU, Bullock MR. Chronic subdural hematomas: current treatment. World Neurosurg 2012;77:49–50. 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, Drever P, Valadka A, Zygun D, Okonkwo D. Multicenter trial of early hypothermia in severe brain injury. J Neurotrauma 2009;26:393–397. 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. Dietrich WD, Bullock MR, Kochanek PM. Hypothermic therapies targeting brain and spinal cord injury. Introduction. J Neurotrauma 2009;26:297–298. Fujita M, Oda Y, Wei EP, Povlishock JT. The combination of either tempol or FK506 with delayed hypothermia: implications for traumatically induced microvascular and axonal protection. J Neurotrauma 2011;28:1209–1218. Fujita M, Wei EP, Povlishock JT. Effects of hypothermia on cerebral autoregulatory vascular responses in two rodent
165 models of traumatic brain injury. J Neurotrauma 2012; 29:1491–1498. 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. Levi AD, Casella G, Green BA, Dietrich WD, Vanni S, Jagid J, Wang MY. Clinical outcomes using modest intravascular hypothermia after acute cervical spinal cord injury. Neurosurgery 2010;66:670–677. Levi AD, Green BA, Wang MY, Dietrich WD, Brindle T, Vanni S, Casella G, Elhammady G, Jagid J. Clinical application of modest hypothermia after spinal cord injury. J Neurotrauma 2009;26:407–415. Marion D, Bullock MR. Current and future role of therapeutic hypothermia. J Neurotrauma 2009;26:455–467. Oda Y, Gao G, Wei EP, Povlishock JT. Combinational therapy using hypothermia and the immunophilin ligand FK506 to target altered pial arteriolar reactivity, axonal damage, and blood-brain barrier dysfunction after traumatic brain injury in rat. J Cereb Blood Flow Metab 2011;31:1143–1154. Povlishock JT, Wei EP. Posthypothermic rewarming considerations following traumatic brain injury. J Neurotrauma 2009; 26:333–340. Yokobori S, Frantzen J, Bullock R, Gajavelli S, Burks S, Bramlett H, Dietrich WD. Traumatic Ischemia/Reperfusion Brain Injury: Review of the Literature. Ther Hypothermia Temperature Man 2011;1:185–192.
Cooling Strategies Targeting Trauma Moderator: W. Dalton Dietrich, Ph.D.1 Participants: John T. Povlishock, Ph.D.,2 Guy Clifton, M.D.,3 M. Ross Bullock, M.D., Ph.D.,1 and Michael Y. Wang, M.D., Ph.D.1
Therapeutic hypothermia and temperature management has now been utilized in a variety of clinical situations following neurotrauma. Single as well as multicenter trials have been conducted to evaluate whether therapeutic hypothermia is beneficial in patients following severe traumatic brain injury (TBI). Although early studies indicated that cooling was effective in reducing mortality and improving functional outcome in TBI patients, subsequent multicenter trials including the National Acute Brain Injury Study: Hypothermia (NABIS-H) trials failed to show efficacy. Various publications have provided insight into the complexity of TBI and potential reasons why early cooling was ineffective in these multicenter trials. Recently, therapeutic hypothermia has also been initiated in patients with severe cervical spinal cord injury. Prolonged periods of systemic hypothermia appear in preliminary single institutions programs to be safe, and may improve functional outcome at 1 year. A series of state-of-the-art lectures presented at the 2012 Therapeutic Hypothermia and Temperature Management meeting in Miami brought together experts in the field of brain and spinal cord injury to discuss the use of therapeutic hypothermia in these patient populations. Dr. John Povlishock, Professor and Chair, Department of Anatomy and Neurobiology at the Virginia Commonwealth University, discussed treating diffuse axonal injury with hypothermia and combination approaches. Dr. Povlishock and colleagues have demonstrated that early cooling in models of TBI have a beneficial effect on reducing overall axonal pathology, a hallmark of TBI. More recently, combination approaches where hypothermia is coupled with specific neuroprotective compounds may produce a synergistic effect on outcome were also discussed. Dr. Guy Clifton, Professor of Neurosurgery at the University of Texas, reviewed his recent provocative data regarding subgroup analysis of the various NABIS-H trials. Dr. Clifton and associates have determined in a limited number of subjects that early hypothermia may be most protective in patients undergoing decompression surgery in contrast to diffuse axonal injury. Concepts regarding therapeutic window of cooling protocols depending on what mechanisms were being targeted were emphasized in this discussion. Dr. Ross Bullock, Director of Clinical Neurotrauma in the Department of Neurological Surgery at the University of Miami, emphasized reperfusion injury as a target for early cooling after TBI. Dr. Bullock and colleagues have recently attempted to test Dr. Clifton’s hypothesis regarding whether an animal model of subdural hematoma with evacuation would benefit from a
cooling strategy initiated prior to the decompression surgery. Results seem to support that hypothesis. Finally, Dr. Michael Wang, Professor of Neurological Surgery at the University of Miami, summarized recent progress in spinal cord injury hypothermia trials. Dr. Wang and colleagues have conducted an IRB-approved study where approximately 45 patients with severe cervical spinal cord injury have undergone whole body cooling for 48 hours followed by a slow rewarming phase. Published data indicate safety as well as some degree of efficacy at 1 year. Thus it is clear from these experimental and clinical investigations that therapeutic hypothermia certainly has a place in targeting neurotrauma with a need for further laboratory and clinical investigations to continue to move this experimental therapy forward. Dr. Guy Clifton: In the Japanese ‘‘B-HYPO’’ trial, was the outcome for the evacuated mass lesion group the primary objective, or was that also a post-hoc subgroup analysis, as with the NABIS-H trials? Dr. Ross Bullock: The latter. Exactly as with the NABIS-H trial. As far as I know, Dr. Yokobori is here. He may know the Japanese literature better than me. Any comments Dr. Yokobori? Dr. Shoji Yokobori: The hypothermia study has not yet been published—only personal communication of early data. I hope we can have the publication out by next year. Dr. Guy Clifton: Were the cooling times short in that study— in the Japanese B-HYPO study? Do you know? Dr. Shoji Yokobori: I think 48 to 72 hours was the cooling time. Dr. David Erlinge: Question to Dr. Wang—Why just ASIA A patients in your study? Also, we know from the spinal cord injury model systems that the first reliable ASIA score isn’t for 72 hours. Dr. Michael Wang: That’s a great question, David. The ASIA A was made I think initially when this data collection process
1
Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, Florida. Department of Anatomy and Neurobiology, Medical College of Virginia/Virginia Commonwealth University, Richmond, Virginia. Department of Neurosurgery, University of Texas Medical School at Houston, Houston, Texas.
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was first started 5 years ago, we weren’t really sure that we could prove safety. I think we’ve gotten to the point where we feel that it is a safe intervention. Thus, in our RO1 submission, we are looking at both ASIA As and Bs for that very reason. Of course, if you enroll less severely injured patients, including ASIA B, C, and D, the heterogeneity of the recovery pattern starts to become a concern. Then we start to look at a sample number to power our study, and it is going to be just simply too big and undoable. In our trial, we are looking at A and B because that will mean those who have no movement below the lesion. But great question.
ischemia/reperfusion injury, which you think you may have had a benefit for in NABIS-H II or when you are trying to treat brain edema or both. This is an important consideration in reference to the timing of hypothermia and duration of hypothermia. I wondered if you and the other members of the panel would comment on whether, in a patient with ongoing brain edema, we might require a different strategy and a different duration of therapy than in patients where we are treating pure ischemia/reperfusion, Although this may rarely occur, but as you made the point, sometimes it is the case in TBI.
Question: How frequently are the patients surgically fixed?
Dr. Guy Clifton: That is a great point. I was asked by Dalton to do a review on brain injury trials in hypothermia. In the distinction I made in that review, I discussed these different mechanisms of protection with hypothermia. I separated them out into those that were purely neuroprotective and those that were more purely for treatment of intracranial pressure (ICP), and then a lot of them merged the two. I think this is the reason for the discrepancies that we are seeing in the results. So, what would you do for ICP treatment? Start later and go longer. For neuroprotection, start early and maybe for not so long. We solved the hypotension problem that, as you pointed out from the first, was a problem in NABIS-H I by fluid expansion. But I think the price we paid was more ICP problems. In retrospect, I would have changed the trial by individualizing the period of rewarming to take account of ICP. So I think there are lessons to be learned. I hope future trial designs really make the distinction of which mechanism they are testing or if they are testing both.
Dr. Michael Wang: 100% of our patients are getting decompression surgery. Question: How many days after? Dr. Michael Wang: Almost all the patients are getting decompressed within a day. Question: One day? Dr. Michael Wang: Less than 12 hours in most cases. But definitely within 24 hours. So when you look at the 42% improvement rate, some people are going to look at that and say, well, how do you know this isn’t from your early decompression surgery? So that’s a very good point. These patients are getting early and optimized care as well. Question: My other question regarding your series is whether anyone was extubated during the cooling period? All of them were intubated? Response: No, in fact many of our patients are not intubated. Question: During the period of hypothermia?
Question: I’ve got a question for Dr. Wang. You showed a slide that showed you have a very high rate of atelectasis. I was surprised. But then you told me most patients were not ventilated. So now I understand why they have atelectasis. But if you are cooling them, and you have a risk of pneumonia, and you are not aware atelectasis causes pneumonia, too, why don’t you use continuous positive airway pressure (CPAP) to prevent pneumonia, too?
Dr. Michael Wang: That’s correct. Question: OK. The other question is, after the hypothermia, do you keep the patients normothermic to avoid prolonging of the fever? Dr. Michael Wang: Yes, we do that. We warm them for a 24hour period, and we try to get the cooling catheters out. Question: Is there a normotherapy protocol after the patient has had the catheter removed? Dr. Michael Wang: Are you asking whether we do something to maintain normothermia? Question: Exactly. Dr. Michael Wang: Yes, absolutely. But not necessarily with invasive technique. Dr. Kees Polderman: Dr. Clifton, I enjoyed your talk. The field now has more than 20 years’ experience in TBI trials. I always like to distinguish whether we are trying to treat
Dr. Michael Wang: I think that’s a great point. I think that how you define atelectasis, right, it can be difficult. So our definition is relatively broad. I think that you can get into this point of where you are chasing your tail in terms of categorizing them as having had an adverse event. For example, CPAP has its own particular problems with these patients, as well, in terms of getting them ventilated properly. However, I think if you compare our results with our historical cohort, we are not seeing higher rates of the complications. That’s really the important point. If you look at a single center like ours, and you say, well, we had a 100% rate of atelectasis 6 years ago, as well, then we are not seeing higher rates of atelectasis. Dr. Dalton Dietrich: So Ross and Mike, since you are sitting together, let me ask you a question. Do you see similarities between traumatic brain injury and spinal cord injury in terms of this phenomenon of reperfusion injury that Guy has talked about? If we find out at the end of the day that it’s better to have the patient cooled when you decompress the brain after trauma, will it not also make sense in terms of spinal cord injury to have the patient cooled when you decompress?
164 Dr. Ross Bullock: The difference in the TBI situation is we have ICP to worry about, which we probably don’t have to worry about that in spinal cord injury. But there is the possibility that the swollen spinal cord might be filling that spinal canal and that this early surgery point may play out to be more important. You know, I think the point that Guy makes that ICP control is an extra benefit you get from hypothermia in severe TBI, that’s very true. Absolutely. I think that if one or other trial or if a TBI trial shows benefit with the hypothermia, the timing of decompression of the spinal cord will also be crucially important. Dr. Michael Wang: I agree with everything Ross said. I think the issue with the spinal cord is that we don’t understand the autoregulatory process in the spinal cord very well. I don’t think that it is quite that elegantly appreciated. It would make sense, right? It would make a lot of sense to take that sort of approach. I think that’s the direction we are moving, right? Dr. Dalton Dietrich: So when you decompress the cord, what’s the temperature of the spinal cord normally? Dr. Michael Wang: At University of Miami, it’s 33C. Dr. Guy Clifton: I was going to make a comment regarding diffuse injury. The puzzle is why there is such strong laboratory data on hypothermia protecting against axonal pathology. Dr. Povlishock showed that posttraumatic hypothermia significantly reduced indicators of DAI. However, we failed to demonstrate it clinically. This inconsistency may be due to the time window. I was thinking about this while John was talking. With hematomas, if this ends up proving out, we’ve been given a pass on the window because reperfusion doesn’t start until you get the clot out. You’ve got ischemia before that. So you’ve really been given a prolonged window. We knew in cortical contusion injury, just empirically in the laboratory, that after 90 minutes, hypothermia doesn’t work, at least in our models. I noticed that John was treating at about 15 minutes. I don’t think we could have cooled any faster than we did in NABIS-H II. Logistically, I don’t even think even with intravascular cooling catheters you could; I don’t know how you could get them in any faster. If in fact for diffuse injury, there is a very narrow window that we met with hematomas just because surgeries take place later, then the answer may ultimately be earlier cooling. But if technically you can’t do it, a strategy would be to combine the mitochondrial stabilizers like cyclosporine A with hypothermia in order to buy time. With diffusion injury, there may simply be a window issue that we’ve not been able to solve in a clinical setting. Dr. Dalton Dietrich: So ladies and gentlemen, how easy is it going to be to conduct a combination clinical trial where you have hypothermia plus a drug? Isn’t that going to be relatively difficult to put together? Dr. John Povlishock: Sure, it’s going to be difficult to get together. But again, if we have more enduring preclinical evidence, I think that’s what the NIH wants to see—that you could document a time frame that would be realistic in a human scenario. There would be interest to move forward, but there is also reluctance because each clinical trial that the
EXPERT PANEL DISCUSSION NIH funds costs about 15 million dollars, at least from the NINDS. So this is a very expensive enterprise. I think they want to see evidence of protection in higher-order animals. And I’m quietly confident it can be done. I want to say one thing to Dr. Wang. You discussed a very interesting history of steroids that was very instructive to this audience. When that study was rolled out, Mike Bracken was an epidemiologist who had championed their use. When that was presented to the neurosurgical community, there was really quite a bit of uproar in the audience. Because the reality is, when you looked at the data, those treated patients only had a very subtle change in sensory improvement. It wasn’t motor; it was only a very subtle sensory change. I think that shows you the fallacy of sometimes rushing too soon to treat. There was so much enthusiasm that maybe this treatment would work without the adequate preclinical and clinical data that they launched these multicenter trials. I think, in hypothermia and actually in other cases, we have more robust data. But we are being more careful now and not as reflexive in our response. Dr. Guy Clifton: I’ve got to say that I still remember before that paper was published, a fax showed up on my desk—with the abstract before anybody had ever reviewed the data. You were essentially told that you’re going to get sued if your patients don’t get this treatment. It was instantly adopted, and, as John said, there was a lot of hypertension. Dr. John Povlishock: Dr. Wang, you want to comment? Dr. Michael Wang: Well, we don’t want to reproduce history in that way, and so I think, on a spinal cord front, it is just a very emotional lightening rod, right? The Kevin Everett story where the NFL player received hypothermia after cervical spinal cord injury, I think, was our Miami foray into that. As we move forward, we need to establish a high level of evidence for this intervention, and we need to have good quality trials. The question is how do we fund that? And that’s really the issue here. I think everybody is motivated to do it. Dr. Ross Bullock: One point is that recently a European company came up with a more so-called brain-bioavailable adjunct of cyclosporine. The rumor on the street is that they have high levels of investor funding and that there is interest in trials in Europe. So that may be a way forward—a threearmed trial or placebo: the new cyclosporine A and hypothermia plus cyclosporine A. It’s some kind of a more interesting paradigm like that. Dr. John Povlishock: The drug doesn’t have immunosuppressant properties, so it doesn’t pose a risk to the patient, but it still protects mitochondria. Dr. Dalton Dietrich: David, any words of wisdom from a cardiologist in terms of what cooling strategies we are trying to do in CNS injury? Dr. David Erlinge: Regarding the discussion about reperfusion injury, I definitely think you should cool them before you decompress. It appears to be the right thing to do. Dr. Dalton Dietrich: Any other comments from the audience for our lecturers today? Well, thank you all for being here.
EXPERT PANEL DISCUSSION Thank you all for the presentations. Again, the audience participation was fantastic. Key References for Panel Participants Ahmad FU, Bullock MR. Chronic subdural hematomas: current treatment. World Neurosurg 2012;77:49–50. 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, Drever P, Valadka A, Zygun D, Okonkwo D. Multicenter trial of early hypothermia in severe brain injury. J Neurotrauma 2009;26:393–397. 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. Dietrich WD, Bullock MR, Kochanek PM. Hypothermic therapies targeting brain and spinal cord injury. Introduction. J Neurotrauma 2009;26:297–298. Fujita M, Oda Y, Wei EP, Povlishock JT. The combination of either tempol or FK506 with delayed hypothermia: implications for traumatically induced microvascular and axonal protection. J Neurotrauma 2011;28:1209–1218. Fujita M, Wei EP, Povlishock JT. Effects of hypothermia on cerebral autoregulatory vascular responses in two rodent
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