THERAPEUTIC HYPOTHERMIA AND TEMPERATURE MANAGEMENT Volume 3, Number 1, 2013 ª Mary Ann Liebert, Inc. DOI: 10.1089/ther.2013.1501
Managing Hypothermia During Organ Transplantation and Cardiac Arrest Moderator: Samuel A. Tisherman, MD1 Participants: Joseph P. Ornato, MD,2 Mary Ann Peberdy, MD,2 and Samuel A. Tisherman, MD1
Therapeutic hypothermia is now used in some organ transplantation procedures and out-of-hospital cardiac arrest patients to reduce mortality and improve functional outcome. Multiple studies have demonstrated the benefits of this therapeutic intervention that has significantly changed the way we practice medicine in this respect. Continued work in this field is providing valuable information regarding how best to administer treatments, as well as some of the risk factors and long-term outcome assessment strategies that are required. 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 therapeutic hypothermia targeting organ transplantation and cardiac arrest. Dr. Samuel Tisherman, Department of Critical Care Medicine and Surgery, Neurotrauma ICU and Associate Director of the SAFAR Center for Resuscitation Research, University of Pittsburgh, PA, presented data regarding the use of therapeutic hypothermia in organ transplantation. Dr. Tisherman discussed some of the mechanisms underlying organ rejections, as well as the COOL donor study to assess the feasibility and safety of mild to moderate hypothermia as an in vivo organ preservation strategy compared to normothermic conditions. He also provided information regarding the use of a Safety Monitoring Committee and overall procedures involved in this investigation. Dr. Jospeh Ornato, Professor of Emergency Medicine and Internal Medicine at Virginia Commonwealth University, provided a comprehensive review of developing and operating a comprehensive postresuscitation system of care. Dr. Ornato discussed various approaches to bringing together important players in terms of providing the best care for postcardiac arrest patients, including the use of therapeutic hypothermia. Dr. Mary Peberdy, Department of Internal Medicine and Emergency Medicine at Virginia Commonwealth University, discussed the development and strategies for operating a comprehensive multidisciplinary care for postarrest patients. Specifically, Dr. Peberdy provided informative information regarding going beyond therapeutic hypothermia and what other steps are being done to enhance protection and recovery of function in this patient population. Potential strategies for reducing reperfusion injury and providing maximum protection against free radical generation were summarized.
variances in terms of whether or not to harvest an organ from a certain donor based upon the transplant surgeon’s choices. It seems to me on my end, while not terribly involved with this field, that sometimes it’s inexplicably variable. Dr. Samuel Tisherman: So you’re trying to explain surgeon behavior. You’re right, it’s an important thing, and I think that they are not blinded to what we are doing because we tell them what is happening. So whether that will play into the decision-making process, I don’t know. It is an important variable that should be more standardized. I think there are some set criteria obviously, but it’s always up to the individuals. I know that when I’m standing there working with our coordinators from our OPO and they are calling around trying to find out if someplace or another will take certain organs from patients, it’s a real concern. They know which one will take the organs so they understand the variability. Question: Some comments for Dr. Ornato. Basically, we started our paramedic serve crew program back in Tampa in 1972. We would send EKGs to the ICU and CCU and defibrillate on the street. Then in 2002, our group looked at the landmark articles from the New England Journal of Medicine, and we thought that was significant enough for us to move ahead with hypothermic therapy, and basically took it to the MS Council. At that time, they said there was not enough information to support this experimental treatment, so we actually put this into community hospitals. We realized right off that we needed some standardization. So we created a course called advanced hypothermic life support that was like a 3.5 hour course, and we put that on in all our hospitals, 18 acute care hospitals for ISIS healthcare. We were able to get buy-in from all the community hospitals because it was very exciting to have new things and to be doing new stuff. We formed our own little club and created the American Society of Hypothermic Medicine, and we all joined in subscribing to the magazine and having our own council and symposia and so forth. So I think there is a void for community hospitals being active. We would actually send patients to the hospital, and they would go to the
Question: Dr. Tisherman, this question’s for you. How big a problem do you think it is regarding individual decision 1
Department of Critical Care Medicine and Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Department of Emergency Medicine and Internal Medicine at Virginia Commonwealth University, Richmond, Virginia.
2
7
8 regional center and would take everything off and say, ‘‘Doctor, we don’t cool our patients here, that’s not part of our protocol.’’ So it could go just the opposite way. I just wanted to mention that. Dr. Joseph Ornato: Well, thanks for your comments, and bravo on the evolution of your program. I’ve been an EMS medical director since 1974. I’m very proud to hear, but not surprised, that what has occurred in your community is actually pretty typical. One of the neat things about EMS in the last 10, 20, 30 years is that, little by little, it’s gone from being an extension of the hospital to, in some areas, the leader of putting in place programs that then stimulate the hospitals to catch up. In our community, we were the first to cool patients at our particular hospital starting in 2003. It wasn’t until 2008 that we diverted the first single patient from what would have been one of the community hospitals to ours because, by then, no one else was offering therapy, and we were clearly seeing an improvement in survival. Within about 2 weeks, every hospital in the entire region had downloaded a protocol off the Internet and had started a hypothermia program. Comment: I think there is something to be said for standardization and having some kind of implementation classes. Dr. Joseph Ornato: You know, I can’t disagree with that. Again, the only place I might have a little difference in philosophy is this whole issue of volume. Question: I have a question for Dr. Peberdy. I really enjoyed your talk. I have some comments on the study that you showed with the hypoxia and hyperoxia. A very large study, very interesting on a number of levels. I don’t fully agree that hypoxia is a good thing because the study showed that both hypoxia and hyperoxia were bad, so normal is good. I would make the point that under hypothermia, the oxygen content of the blood is lower, so if your PO2 is like 70, the real value at 33 is 50. So I don’t want people to go away with the impression that hypoxia is a good thing. Another point from that study is that it shows that we have a lot of work to do because only 6% of patients apparently were cooled in that 6,000-patient study or had the lowest recorded temperature below 34C. Some of those cooled patients were probably accidental as well. Dr. Mary Ann Peberdy: Yes, you are absolutely right about the hypoxia. In most experimental models, hypoxia itself is bad. But you are right, the oxygen utilization/oxygen consumption is reduced so much when people are hypothermic that they can tolerate some relative hypoxia for a short period of time better than if they were normothermic. Dr. Joseph Ornato: I agree. In the second studies you summarized with a registry from Australia and New Zealand that could not show harm from hyperoxia, but they did document evidence of harm with hypoxia. So it clearly would support the point you are making. Question: Two brief questions, one for Dr. Tisherman. The study on the transplantation cooling study, will you be informing the recipients that their organs are part of a trial? Will you be consenting the recipients to see whether the
EXPERT PANEL DISCUSSION likelihood of rejection goes down once this inflammatory component is washed out of their organs? Dr. Samuel Tisherman: That’s a good question that has been brought up before. I think my understanding of the way the study is set up at the moment is that they will not be. However, the transplant recipient surgeons will be told about it, but there won’t be consent from the recipient to receive the organ or not. They may be told about it, but that is one of the questions that has been brought up about any kind of research on donors—whether you should be informing the recipient. Question: And a second question for Dr. Peberdy, you talked about the stunned myocardium being a sympathetically driven phenomenon from the brain. We’ve also seen this phenomenon in subarachnoid hemorrhage and trauma patients. There are also data, as you know better than I, that doses of epinephrine used during resuscitation correlate with mortality. When you control for duration of resuscitation, do you know whether there is any effect of epinephrine dose on survival. In other words, obviously the longer you have to resuscitate, the more doses you are going to give of epinephrine. But given equal doses of epinephrine, is it a negative survival predictor? Dr. Joseph Ornato: The longer the resuscitation attempts continue, the more epinephrine doses will have been given, thus selecting out patients who may have return of spontaneous circulation but will likely have a poor prognosis due to the prolonged ischemic time interval. One of the real questions behind what you just asked is do any of these drugs make any difference in resuscitation? There is a wonderful paper that made the New England Journal of Medicine about 18 months ago from researchers in Norway who conducted a randomized trial prehospital with defibrillation, CPR, and the standard ACLS drugs versus none of the ACLS drugs, including epinephrine, lidocaine, amiodrone, and so on. There was an improvement in return of spontaneous circulation (ROSC) and survival to admission in the group that got the drugs, but with the number of patients that they had, it did not turn out to be statistically significant in terms of the number of patients that survived to discharge. There was a trend in favor of it being better. I think it’s still an important unknown question, and there’s a lot of debate between our European and American colleagues. But there is another part to the story. You are absolutely right, and we are firm believers from the data currently in animals and humans—the brain is driving a lot of what is going on in the heart. You know, the EEG during resuscitation at the surface looks silent. There are about eight cases in the literature that had arrests during EEG monitoring, usually in the neurosurgical literature. It goes flat right away, within 20–30 seconds of starting CPR. But lower down, interesting things are happening. We’ve got data in an animal model where we induce VF at the end of euthanasia where we’ve got probes in the sympathetic nerves surrounding the renal artery. Within a couple of seconds of inducing VF and the heart stopping, you get sympathetic storm. Question: Dr. Tisherman, this is an interesting study on preserving the organs for transplantation. First analogy, in Spain they use the Lucas device for cardiac compressions to
EXPERT PANEL DISCUSSION preserve the circulation in patients only to protect the organs to be used for transplantations. The funny thing was that a couple of those patients survived. So be careful when you choose new potent therapies. But the question is I think it’s very logical preserving the organs. Protecting them with hypothermia would be very good and has great potential of succeeding in this trial. But the real important question is when you reperfused the organs. That’s when you need the hypothermia. So maybe you should cool the recipient patient for a couple of hours after transplantation. Dr. Samuel Tisherman: That might be the next study. Good point, thank you. Question: Dr. Peberdy, I really enjoyed your presentation. But I was very interested in your comment that in patients with cardiac arrest, you basically thought there was no cerebral autoregulation. Thus, you would go with pressors and raise blood pressure, but one really wonders in ischemic brain what the intracranial pressure [ICP] is. Has there been any attempt at monitoring cerebral perfusion pressure in these patients? Dr. Mary Ann Peberdy: That’s a loaded question. You are absolutely right that the mean arterial pressure has to take into a balance what the ICP is. In most of the postarrest patients, no invasive monitoring is conducted. However, just looking at the scans, cerebral edema does not appear to play a big role. So we as nonneurointensivists try to take care of these patients as soon as we can drive MAP because ICP is not playing a big role. There are not any studies that have looked at invasive monitoring in this patient population on a large clinical basis. I’d love to hear the thoughts of others, but some of the feedback that we are getting is that we get their temperature down so rapidly that putting something invasive into a brain that is at 33C or 34C raises the intercranial bleed rate. So I think that may be one limitation as to why there is not more invasive data. Our neurointensivists laugh at us on a regular basis because we take care of people with a huge brain injury without having any idea of actually what is going on with the brain. Question: I have a follow-up, just a very quick question. Obviously, you are sort of revisiting the issue of secondary cascades of reperfusion injury, which have been studied by many people in this room. Many of us studying traumatic brain injury advocated the use of radical scavengers. The fact is that our institution 30 years ago conducted a clinical trial using superoxide dismutase that failed miserably because we pegulated it. I really wonder if you could use native superoxide dismutase, particularly in these patients because (1) it’s safe and (2) the barrier has to be broached so it enters the brain parenchyma. You may get double-protective effects. Dr. Mary Ann Peberdy: It’s a very interesting comment, and I think the only free-radical scavenger that has even in small numbers been shown clinically to have potentially some benefit is actually Co-Q10 in this patient population. Question: So just to follow up to the question about invasive monitoring. At Columbia, we have a series of 15 patients that we’re putting together where we put in invasive monitoring
9 in the brain. Multimodality monitoring includes microdialysis, brain tissue oxygenation, and jugular venous oxygenation. We have found that MAP certainly drives PCO2, and ventilation is the other big driver. So hyperventilation and adequate MAP seem to be important in terms of brain tissue health. The other phase that surprised us somewhat was that rewarming can be a complicated process concerning the brain. Certainly, we know it’s a concern systemically, but we see a lot of metabolic distress during rewarming to the point where it basically halts our rewarming in many cases. We just stop. Dr. Joseph Ornato: What rewarming protocol are you using? Response: Typically 0.25 an hour. We’ve occasionally gone to 0.1 an hour. Question: I was just going to comment that in most of the experimental animal studies in cardiac arrest, there really is not much blood–brain barrier permeability. So I think if you were to use an antioxidant, I’d want to use a small molecule. I think some people think there is a lot of blood–brain barrier permeability after cardiac arrest, but there really isn’t much. Response: I would say during reperfusion, there is tremendous opening of the blood–brain barrier. Response: The blood–brain barrier changes in cardiac arrest models are relatively unremarkable. We’ve looked really hard for blood–brain barrier permeability, and it’s maybe with a really small molecule like, you know, GABA or something like that, but with larger molecules, we just don’t see it. Key References from Panel Participants Drabek T, Kochanek PM, Stezoski J, Wu X, Bayir H, Morhard RC, Stezoski SW, Tisherman SA. Intravenous hydrogen sulfide does not induce hypothermia or improve survival from hemorrhagic shock in pigs. Shock 2011;35:67–73. Drabek T, Tisherman SA, Beuke L, Stezoski J, Janesko-Feldman K, Lahoud-Rahme M, Kochanek PM. Deep hypothermia attenuates microglial proliferation independent of neuronal death after prolonged cardiac arrest in rats. Anesth Analg 2009;109:914–923. Fiorello A, Paradis NA, O’Neil BJ. A randomized controlled trial comparing the Arctic Sun to standard cooling for induction of hypothermia after cardiac arrest. Resuscitation 2009;81:9–14. Heard KJ, Peberdy MA, Sayre MR, Sanders A, Geocadin RG, Dixon SR, Larabee TM, Hiller K, Suffoletto B, Peberdy MA, van der Hoek T, Callaway C. Body temperature changes are associated with outcomes following in-hospital cardiac arrest and return of spontaneous circulation. Resuscitation 2009;80: 1365–1370. Huynh N, Kloke J, Gu C, Callaway CW, Guyette FX, Gebhardt K, Alvarez R, Tisherman SA, Rittenberger JC. The effect of hypothermia ‘‘dose’’ on vasopressor requirements and outcome after cardiac arrest. Resuscitation 2012; Epub ahead of print. Kochanek PM, Drabek T, Tisherman SA. Therapeutic hypothermia: the Safar vision. J Neurotrauma 2009;26:417–420.
10 Mechem CC, Goodloe JM, Richmond NJ, Kaufman BJ, Pepe PE; U.S. Metropolitan Municipalities EMS Medical Directors Consortium. Resuscitation center designation: recommendations for emergency medical services practices. Prehosp Emerg Care 2010;14:51–61. Merchant RM, Abella BS, Peberdy MA, Soar J, Ong ME, Schmidt GA, Becker LB, Vanden Hoek TL. Therapeutic hypothermia after cardiac arrest: unintentional overcooling is common using ice packs and conventional cooling blankets. Crit Care Med 2006;34:S490–494. Ornato JP. Special resuscitation situations: near drowning, traumatic injury, electric shock, and hypothermia. Circulation 1986;74:IV23–26.
EXPERT PANEL DISCUSSION Ornato JP, Kurz MC, Peberdy MA. Controlling reperfusion injury: role of induced hypothermia in post-resuscitation care. JEMS 2009;34:17–20. Stone GW, Vora K, Schindler J, Diaz C, Mann T, Dangas G, Best P, Cutlip DE; COOL-RCN Investigators. Systemic hypothermia to prevent radiocontrast nephropathy (from the COOLRCN Randomized Trial). Am J Cardiol 2011;108:741–746. Tisherman SA. When it comes to hypothermia and trauma: kids are really little adults. Pediatr Crit Care Med 2010;11:301–302. Tisherman SA. The yin and yang of hypothermia in trauma. J Intensive Care Med 2010;25:240–242. Tisherman SA. Spontaneous cooling and rewarming after cardiac arrest may not be therapeutic. Resuscitation 2012;83:283–284.
Managing Hypothermia During Organ Transplantation and Cardiac Arrest Moderator: Samuel A. Tisherman, MD1 Participants: Joseph P. Ornato, MD,2 Mary Ann Peberdy, MD,2 and Samuel A. Tisherman, MD1
Therapeutic hypothermia is now used in some organ transplantation procedures and out-of-hospital cardiac arrest patients to reduce mortality and improve functional outcome. Multiple studies have demonstrated the benefits of this therapeutic intervention that has significantly changed the way we practice medicine in this respect. Continued work in this field is providing valuable information regarding how best to administer treatments, as well as some of the risk factors and long-term outcome assessment strategies that are required. 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 therapeutic hypothermia targeting organ transplantation and cardiac arrest. Dr. Samuel Tisherman, Department of Critical Care Medicine and Surgery, Neurotrauma ICU and Associate Director of the SAFAR Center for Resuscitation Research, University of Pittsburgh, PA, presented data regarding the use of therapeutic hypothermia in organ transplantation. Dr. Tisherman discussed some of the mechanisms underlying organ rejections, as well as the COOL donor study to assess the feasibility and safety of mild to moderate hypothermia as an in vivo organ preservation strategy compared to normothermic conditions. He also provided information regarding the use of a Safety Monitoring Committee and overall procedures involved in this investigation. Dr. Jospeh Ornato, Professor of Emergency Medicine and Internal Medicine at Virginia Commonwealth University, provided a comprehensive review of developing and operating a comprehensive postresuscitation system of care. Dr. Ornato discussed various approaches to bringing together important players in terms of providing the best care for postcardiac arrest patients, including the use of therapeutic hypothermia. Dr. Mary Peberdy, Department of Internal Medicine and Emergency Medicine at Virginia Commonwealth University, discussed the development and strategies for operating a comprehensive multidisciplinary care for postarrest patients. Specifically, Dr. Peberdy provided informative information regarding going beyond therapeutic hypothermia and what other steps are being done to enhance protection and recovery of function in this patient population. Potential strategies for reducing reperfusion injury and providing maximum protection against free radical generation were summarized.
variances in terms of whether or not to harvest an organ from a certain donor based upon the transplant surgeon’s choices. It seems to me on my end, while not terribly involved with this field, that sometimes it’s inexplicably variable. Dr. Samuel Tisherman: So you’re trying to explain surgeon behavior. You’re right, it’s an important thing, and I think that they are not blinded to what we are doing because we tell them what is happening. So whether that will play into the decision-making process, I don’t know. It is an important variable that should be more standardized. I think there are some set criteria obviously, but it’s always up to the individuals. I know that when I’m standing there working with our coordinators from our OPO and they are calling around trying to find out if someplace or another will take certain organs from patients, it’s a real concern. They know which one will take the organs so they understand the variability. Question: Some comments for Dr. Ornato. Basically, we started our paramedic serve crew program back in Tampa in 1972. We would send EKGs to the ICU and CCU and defibrillate on the street. Then in 2002, our group looked at the landmark articles from the New England Journal of Medicine, and we thought that was significant enough for us to move ahead with hypothermic therapy, and basically took it to the MS Council. At that time, they said there was not enough information to support this experimental treatment, so we actually put this into community hospitals. We realized right off that we needed some standardization. So we created a course called advanced hypothermic life support that was like a 3.5 hour course, and we put that on in all our hospitals, 18 acute care hospitals for ISIS healthcare. We were able to get buy-in from all the community hospitals because it was very exciting to have new things and to be doing new stuff. We formed our own little club and created the American Society of Hypothermic Medicine, and we all joined in subscribing to the magazine and having our own council and symposia and so forth. So I think there is a void for community hospitals being active. We would actually send patients to the hospital, and they would go to the
Question: Dr. Tisherman, this question’s for you. How big a problem do you think it is regarding individual decision 1
Department of Critical Care Medicine and Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Department of Emergency Medicine and Internal Medicine at Virginia Commonwealth University, Richmond, Virginia.
2
7
8 regional center and would take everything off and say, ‘‘Doctor, we don’t cool our patients here, that’s not part of our protocol.’’ So it could go just the opposite way. I just wanted to mention that. Dr. Joseph Ornato: Well, thanks for your comments, and bravo on the evolution of your program. I’ve been an EMS medical director since 1974. I’m very proud to hear, but not surprised, that what has occurred in your community is actually pretty typical. One of the neat things about EMS in the last 10, 20, 30 years is that, little by little, it’s gone from being an extension of the hospital to, in some areas, the leader of putting in place programs that then stimulate the hospitals to catch up. In our community, we were the first to cool patients at our particular hospital starting in 2003. It wasn’t until 2008 that we diverted the first single patient from what would have been one of the community hospitals to ours because, by then, no one else was offering therapy, and we were clearly seeing an improvement in survival. Within about 2 weeks, every hospital in the entire region had downloaded a protocol off the Internet and had started a hypothermia program. Comment: I think there is something to be said for standardization and having some kind of implementation classes. Dr. Joseph Ornato: You know, I can’t disagree with that. Again, the only place I might have a little difference in philosophy is this whole issue of volume. Question: I have a question for Dr. Peberdy. I really enjoyed your talk. I have some comments on the study that you showed with the hypoxia and hyperoxia. A very large study, very interesting on a number of levels. I don’t fully agree that hypoxia is a good thing because the study showed that both hypoxia and hyperoxia were bad, so normal is good. I would make the point that under hypothermia, the oxygen content of the blood is lower, so if your PO2 is like 70, the real value at 33 is 50. So I don’t want people to go away with the impression that hypoxia is a good thing. Another point from that study is that it shows that we have a lot of work to do because only 6% of patients apparently were cooled in that 6,000-patient study or had the lowest recorded temperature below 34C. Some of those cooled patients were probably accidental as well. Dr. Mary Ann Peberdy: Yes, you are absolutely right about the hypoxia. In most experimental models, hypoxia itself is bad. But you are right, the oxygen utilization/oxygen consumption is reduced so much when people are hypothermic that they can tolerate some relative hypoxia for a short period of time better than if they were normothermic. Dr. Joseph Ornato: I agree. In the second studies you summarized with a registry from Australia and New Zealand that could not show harm from hyperoxia, but they did document evidence of harm with hypoxia. So it clearly would support the point you are making. Question: Two brief questions, one for Dr. Tisherman. The study on the transplantation cooling study, will you be informing the recipients that their organs are part of a trial? Will you be consenting the recipients to see whether the
EXPERT PANEL DISCUSSION likelihood of rejection goes down once this inflammatory component is washed out of their organs? Dr. Samuel Tisherman: That’s a good question that has been brought up before. I think my understanding of the way the study is set up at the moment is that they will not be. However, the transplant recipient surgeons will be told about it, but there won’t be consent from the recipient to receive the organ or not. They may be told about it, but that is one of the questions that has been brought up about any kind of research on donors—whether you should be informing the recipient. Question: And a second question for Dr. Peberdy, you talked about the stunned myocardium being a sympathetically driven phenomenon from the brain. We’ve also seen this phenomenon in subarachnoid hemorrhage and trauma patients. There are also data, as you know better than I, that doses of epinephrine used during resuscitation correlate with mortality. When you control for duration of resuscitation, do you know whether there is any effect of epinephrine dose on survival. In other words, obviously the longer you have to resuscitate, the more doses you are going to give of epinephrine. But given equal doses of epinephrine, is it a negative survival predictor? Dr. Joseph Ornato: The longer the resuscitation attempts continue, the more epinephrine doses will have been given, thus selecting out patients who may have return of spontaneous circulation but will likely have a poor prognosis due to the prolonged ischemic time interval. One of the real questions behind what you just asked is do any of these drugs make any difference in resuscitation? There is a wonderful paper that made the New England Journal of Medicine about 18 months ago from researchers in Norway who conducted a randomized trial prehospital with defibrillation, CPR, and the standard ACLS drugs versus none of the ACLS drugs, including epinephrine, lidocaine, amiodrone, and so on. There was an improvement in return of spontaneous circulation (ROSC) and survival to admission in the group that got the drugs, but with the number of patients that they had, it did not turn out to be statistically significant in terms of the number of patients that survived to discharge. There was a trend in favor of it being better. I think it’s still an important unknown question, and there’s a lot of debate between our European and American colleagues. But there is another part to the story. You are absolutely right, and we are firm believers from the data currently in animals and humans—the brain is driving a lot of what is going on in the heart. You know, the EEG during resuscitation at the surface looks silent. There are about eight cases in the literature that had arrests during EEG monitoring, usually in the neurosurgical literature. It goes flat right away, within 20–30 seconds of starting CPR. But lower down, interesting things are happening. We’ve got data in an animal model where we induce VF at the end of euthanasia where we’ve got probes in the sympathetic nerves surrounding the renal artery. Within a couple of seconds of inducing VF and the heart stopping, you get sympathetic storm. Question: Dr. Tisherman, this is an interesting study on preserving the organs for transplantation. First analogy, in Spain they use the Lucas device for cardiac compressions to
EXPERT PANEL DISCUSSION preserve the circulation in patients only to protect the organs to be used for transplantations. The funny thing was that a couple of those patients survived. So be careful when you choose new potent therapies. But the question is I think it’s very logical preserving the organs. Protecting them with hypothermia would be very good and has great potential of succeeding in this trial. But the real important question is when you reperfused the organs. That’s when you need the hypothermia. So maybe you should cool the recipient patient for a couple of hours after transplantation. Dr. Samuel Tisherman: That might be the next study. Good point, thank you. Question: Dr. Peberdy, I really enjoyed your presentation. But I was very interested in your comment that in patients with cardiac arrest, you basically thought there was no cerebral autoregulation. Thus, you would go with pressors and raise blood pressure, but one really wonders in ischemic brain what the intracranial pressure [ICP] is. Has there been any attempt at monitoring cerebral perfusion pressure in these patients? Dr. Mary Ann Peberdy: That’s a loaded question. You are absolutely right that the mean arterial pressure has to take into a balance what the ICP is. In most of the postarrest patients, no invasive monitoring is conducted. However, just looking at the scans, cerebral edema does not appear to play a big role. So we as nonneurointensivists try to take care of these patients as soon as we can drive MAP because ICP is not playing a big role. There are not any studies that have looked at invasive monitoring in this patient population on a large clinical basis. I’d love to hear the thoughts of others, but some of the feedback that we are getting is that we get their temperature down so rapidly that putting something invasive into a brain that is at 33C or 34C raises the intercranial bleed rate. So I think that may be one limitation as to why there is not more invasive data. Our neurointensivists laugh at us on a regular basis because we take care of people with a huge brain injury without having any idea of actually what is going on with the brain. Question: I have a follow-up, just a very quick question. Obviously, you are sort of revisiting the issue of secondary cascades of reperfusion injury, which have been studied by many people in this room. Many of us studying traumatic brain injury advocated the use of radical scavengers. The fact is that our institution 30 years ago conducted a clinical trial using superoxide dismutase that failed miserably because we pegulated it. I really wonder if you could use native superoxide dismutase, particularly in these patients because (1) it’s safe and (2) the barrier has to be broached so it enters the brain parenchyma. You may get double-protective effects. Dr. Mary Ann Peberdy: It’s a very interesting comment, and I think the only free-radical scavenger that has even in small numbers been shown clinically to have potentially some benefit is actually Co-Q10 in this patient population. Question: So just to follow up to the question about invasive monitoring. At Columbia, we have a series of 15 patients that we’re putting together where we put in invasive monitoring
9 in the brain. Multimodality monitoring includes microdialysis, brain tissue oxygenation, and jugular venous oxygenation. We have found that MAP certainly drives PCO2, and ventilation is the other big driver. So hyperventilation and adequate MAP seem to be important in terms of brain tissue health. The other phase that surprised us somewhat was that rewarming can be a complicated process concerning the brain. Certainly, we know it’s a concern systemically, but we see a lot of metabolic distress during rewarming to the point where it basically halts our rewarming in many cases. We just stop. Dr. Joseph Ornato: What rewarming protocol are you using? Response: Typically 0.25 an hour. We’ve occasionally gone to 0.1 an hour. Question: I was just going to comment that in most of the experimental animal studies in cardiac arrest, there really is not much blood–brain barrier permeability. So I think if you were to use an antioxidant, I’d want to use a small molecule. I think some people think there is a lot of blood–brain barrier permeability after cardiac arrest, but there really isn’t much. Response: I would say during reperfusion, there is tremendous opening of the blood–brain barrier. Response: The blood–brain barrier changes in cardiac arrest models are relatively unremarkable. We’ve looked really hard for blood–brain barrier permeability, and it’s maybe with a really small molecule like, you know, GABA or something like that, but with larger molecules, we just don’t see it. Key References from Panel Participants Drabek T, Kochanek PM, Stezoski J, Wu X, Bayir H, Morhard RC, Stezoski SW, Tisherman SA. Intravenous hydrogen sulfide does not induce hypothermia or improve survival from hemorrhagic shock in pigs. Shock 2011;35:67–73. Drabek T, Tisherman SA, Beuke L, Stezoski J, Janesko-Feldman K, Lahoud-Rahme M, Kochanek PM. Deep hypothermia attenuates microglial proliferation independent of neuronal death after prolonged cardiac arrest in rats. Anesth Analg 2009;109:914–923. Fiorello A, Paradis NA, O’Neil BJ. A randomized controlled trial comparing the Arctic Sun to standard cooling for induction of hypothermia after cardiac arrest. Resuscitation 2009;81:9–14. Heard KJ, Peberdy MA, Sayre MR, Sanders A, Geocadin RG, Dixon SR, Larabee TM, Hiller K, Suffoletto B, Peberdy MA, van der Hoek T, Callaway C. Body temperature changes are associated with outcomes following in-hospital cardiac arrest and return of spontaneous circulation. Resuscitation 2009;80: 1365–1370. Huynh N, Kloke J, Gu C, Callaway CW, Guyette FX, Gebhardt K, Alvarez R, Tisherman SA, Rittenberger JC. The effect of hypothermia ‘‘dose’’ on vasopressor requirements and outcome after cardiac arrest. Resuscitation 2012; Epub ahead of print. Kochanek PM, Drabek T, Tisherman SA. Therapeutic hypothermia: the Safar vision. J Neurotrauma 2009;26:417–420.
10 Mechem CC, Goodloe JM, Richmond NJ, Kaufman BJ, Pepe PE; U.S. Metropolitan Municipalities EMS Medical Directors Consortium. Resuscitation center designation: recommendations for emergency medical services practices. Prehosp Emerg Care 2010;14:51–61. Merchant RM, Abella BS, Peberdy MA, Soar J, Ong ME, Schmidt GA, Becker LB, Vanden Hoek TL. Therapeutic hypothermia after cardiac arrest: unintentional overcooling is common using ice packs and conventional cooling blankets. Crit Care Med 2006;34:S490–494. Ornato JP. Special resuscitation situations: near drowning, traumatic injury, electric shock, and hypothermia. Circulation 1986;74:IV23–26.
EXPERT PANEL DISCUSSION Ornato JP, Kurz MC, Peberdy MA. Controlling reperfusion injury: role of induced hypothermia in post-resuscitation care. JEMS 2009;34:17–20. Stone GW, Vora K, Schindler J, Diaz C, Mann T, Dangas G, Best P, Cutlip DE; COOL-RCN Investigators. Systemic hypothermia to prevent radiocontrast nephropathy (from the COOLRCN Randomized Trial). Am J Cardiol 2011;108:741–746. Tisherman SA. When it comes to hypothermia and trauma: kids are really little adults. Pediatr Crit Care Med 2010;11:301–302. Tisherman SA. The yin and yang of hypothermia in trauma. J Intensive Care Med 2010;25:240–242. Tisherman SA. Spontaneous cooling and rewarming after cardiac arrest may not be therapeutic. Resuscitation 2012;83:283–284.
