Intraoperative Temperature Management

Moderator: W. Dalton Dietrich, PhD1

Participants: M. Ross Bullock, MD, PhD,1 Justin B. Lundbye, MD,2 and W. Dalton Dietrich, PhD1

The use of cooling strategies and targeted temperaturemanagement approaches in treating patients in the in-traoperative or ICU setting is an area of active investigation.Significant animal experimentation has shown that main-taining normothermia or reducing temperature to mild levelsof hypothermia can improve outcomes in a number of ex-perimental settings. An emerging controversial area for fu-ture investigation is the depth of hypothermia that is neededto promote neuroprotection and improve recovery. Thus, aseries of state-of-the-art lectures presented at the 2014Therapeutic Hypothermia and Temperature Managementmeeting in Miami brought together experts in the field ofcritical care and temperature management targeting cardiacarrest, traumatic brain injury (TBI), as well as spinal cordinjury (SCI). Dr. Ross Bullock, Professor, Department ofNeurological Surgery at the University of Miami MillerSchool of Medicine, presented recent studies indicating thatinduced mild hypothermia prior to decompression surgery inan animal model of subdural hematoma appears to protectthe brain from secondary injury mechanisms. In contrast tocooling after TBI, which has been shown to be beneficial insome cases, cooling prior to surgical decompression appearsto reduce secondary injury mechanisms associated with re-perfusion injury in a rat model. Based on these observations,a multicenter trial is now being initiated to test this earlycooling strategy in the specific population of acute subduralhematoma in severe TBI patients (HOPES Study). Dr. JustinLundbye, chief of cardiology, Hospital of Central Connecti-cut, New Britain, Connecticut, provided an interesting pre-sentation on how to cool pulseless electrical activity (PEA)and asystole patients. Specific discussions centered aroundspecific patients who may present with chronic hypoxia orhypotension that could require extensive stabilizationprocedures prior to initiating hypothermia. A very rich dis-cussion focused on the recent Scandinavian targeted tem-perature management clinical study that indicated noadditional beneficial effects of reducing temperature to 33 ascompared to 36�. Dr. Dalton Dietrich, scientific director ofThe Miami Project to Cure Paralysis, University of Miami,updated the attendees on current research regarding thera-peutic hypothermia in severe SCI patients. Previous studiesconducted in many laboratories throughout the world have

shown that relatively mild reductions in temperature arebeneficial in terms of reducing histopathological damage andfunctional improvement in animal models of SCI. More re-cently, clinical studies conducted in single institutions havereported that systemic hypothermia in severe SCI patients isrelatively safe and associated with some indications of im-proved outcome. Indeed, both systemic and local hypother-mia appear to have beneficial effects in various patientpopulations. The need for a randomized multicenter trial toevaluate therapeutic hypothermia is currently needed.

Question: My question, Dr. Dietrich, is in reference to yourstatement that we should always refer back to the animalliterature to see what that showed in terms of going forward.How do we interpret recent results from studies in post-cardiac arrest patients when the animal literature typicallyhas shown that 32 and 34� or even colder is beneficialcompared to normothermia?

Dr. Dalton Dietrich: I think that’s an important question thatthe field may now have to deal with. It may be due to severalfactors; it’s all about the patient population, and we justmentioned differences in patient populations, some beingmore beneficial in terms of hypothermia. The clinical find-ings are important because we can study those data and takethem back to the laboratory and try to mimic specifically thepatient population that was investigated in that particularregard. Before I turn the microphone over to my colleagues tohelp address the question, I think that point of overlap be-tween the two temperatures is also critical. You wouldprobably get the same result in the laboratory if that overlapwas not very different in two groups. So that is just one thingthat I would consider in terms of going back to the animalmodel literature.

Dr. Justin Lundbye: I think that is a great question, and Ithink we are all struggling with that a little bit. I mean, it isvery easy to sit up here and obviously point out all the flaws ofthe study because it really was a well-designed and very well-executed study. The temperature is one thing. The emergencymedical services (EMS) system in Europe, as you know, is alittle bit different: the response time, the incidence of

1Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, Florida.2Hospital of Central Connecticut, New Britain, Connecticut.

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bystander cardiac pulmonary resuscitation (CPR), coolingtechnique, and temperature control looking at the variabilitybetween the two groups. It was significant. I think, not crit-icizing the study, that there was a big sway in the temperatureof these two patient populations, so it’s hard to take that leapfor me and say that we should go to 36� based on that.

Question: Dr. Kumar from India is using electromagneticfields to restore cartilage in knees. Do you do any researchon Schwann cells using electromagnetic fields?

Dr. Dalton Dietrich: No, we do not. It’s an interesting topicand something that scientists are investigating. There arescientists, for example, showing the effects of electrical fieldson fibroblast morphology and genetic composition. So itappears that electromagnetic fields can change the phenotypeof a cell. It appears that this type of approach might also workin terms of enhancing the phenotype of a Schwann cell torelease growth factors or potentially enhance remyelination.Our Schwann cell transplant is like a first step, and then weare going to try to build on combination approaches. How-ever, every time we try to add something to the treatment, theFDA wants additional evidence for safety and efficacy. Somaybe electrical fields are something that would probably nothave any risk factors. Currently, the SCI field is also assessingepidural stimulation. We are looking at different types ofmatrix materials in which we can place the Schwann cells topromote survival and integration. So there are a lot of ex-citing things going on in the field.

Dr. Ross Bullock: If I could just chime in on that, I think thatthis is a field in which there is a tremendous amount of in-terest right now. There’s pulsed electromagnetic stimulation,there’s magnetic stimulation, there’s direct current. There arealso different types of current frequencies. Then there’s theissue of current and magnetic field penetration into the ner-vous system. I think most orthopedic surgeons would agreethat some types of electrical stimulation enhance ossificationand probably fibroblast proliferation in terms of woundhealing. But in the CNS, the whole area is much less clearlyunderstood. So how are we going to make forward progress?One thing that is clear is that the FDA in the United States hasa much more lenient approach to devices than they do todrugs. So of course, these stimulation companies have a bigadvantage. All they have to prove is that the device doesn’tharm anybody and that they are equivalent to some otherdevice for bone healing.

Comment: A couple of points on the temperature depth andduration and what is known from preclinical studies. Avail-able data from most studies come from young healthy ani-mals that have no comorbid diseases. One of the issues intranslating animal data to patients especially with strokes andto a lesser extent cardiac arrest is that they do not have age,diabetes, hypertension, and other problems. I think one of thethings we all have to do is go back to the lab with models thatinclude age and at least hypertension, if not diabetes, to try toanswer this question. The point that Justin made about IVsaline bolus is relevant because there are some complications,certainly in the stroke patients from the extra fluid, and youshowed data from the cardiac arrest patients that we didn’texpect based on animal studies. We just looked at our data,

which we have not published yet, comparing ICTUS II toICTUS L. The biggest difference between the two protocolswas the presence of the saline bolus in ICTUS II—samecatheter, same antishivering protocol. Basically, the samepatient population. The ICTUS II patients were slightlyheavier. We could not show any advantage of 2-liter bolus oficed saline in terms of time to target. It was spot-on identicalin terms of time to reach target. Now one confounding pointis that we are using a very powerful cooling catheter, and itmay not be necessary to use the iced saline with that catheter.It might be with other methods, but we didn’t see any of theharm that you showed in the cardiac arrest patients. We didn’tsee fluid overload, congestive heart failure, or an increasedincidence of afib. So I’m not sure it’s hurting anybody, but wecould not show any benefit.

Question: I have a brief comment and then a question forDr. Lundbye. I think in regard to the recent Scandinavianstudy, and a comment that the European population isdifferent and the results of the TTM trial may therefore notbe transferable to the United States, I want to remind ev-erybody that the HACA study was done in Europe, and wetranslated that immediately to the United States. The Ber-nard study was done in Australia, and we translated thatimmediately to the United States because of the favor-able outcomes. I think rather than trying to focus on thedifferences between our two populations, we need to un-derstand a little bit better what was going on in the resus-citation of these patients that has changed over the last 12years. How does temperature modulation impact criticalcare that is considerably different from it was a decade ago.I think almost any study has shown that the control groupsare looking better, and it does in about any intervention wedo. I think it is the understanding that the overall treatmentis changing—that’s the important part, and not whetherthere are transatlantic or transpacific differences. Thequestion I had for Dr. Lundbye has to do with the PEAasystoles. Have you noticed a difference in the proportion ofpatients undergoing percutaneous coronary interventionnow compared to a decade ago? Rather than strictly at-tributing improvements to the fact that we’re cooling, and Ibelieve in cooling, is it a fact that you are actually treatingthese patients? We’ve seen this definitely in high-gradesubarachnoid hemorrhage now. We treat the grade 4s and5s, and our outcomes are considerably better than they werea decade ago. Because today you don’t just say this is ahopeless population. Have you compared acute interven-tions in these patients plus hypothermia? Whether or notthat is making a difference too?

Dr. Justin Lundbye: I think that is a great question, but it ismore pertinent in the fibrillating population because that iswhere you tend to see the ischemic-driven arrests. We havenot looked at this group, but I’d be very curious to do that. Wecan very easily do that to see if there has been a trend shift inthe way we take these patients to the cardiac catheter lab andif we intervene on them.

Question: Just to comment a little bit on the temperaturecurves of the TTM trial. It is all about how you present data.If you read the article properly and thoroughly, you can seethere are two standard deviations shown in that graph. So

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you don’t need a statistical test at all to show that it is clearlyseparated. If you look at the time points, they are separatedstatistically from a level of p = 0.001 at every time pointexcept the first. I can show you tomorrow some graphswhere we can use one standard deviation; it will look muchmore impressive.

Comment: In terms of the prehospital hypothermia and lackof effect, we talked about the fluid bolus as a potential con-founder. We also mentioned in a separate discussion, I be-lieve, the importance of rewarming and how it can causeharm in working with a STEMI program and EMS. We havepatients come into the emergency room and the cath lab withice packs under their armpits and everything else to try to dothat. Is there preclinical data to suggest this is a good prac-tice? One of the things I’m worried about is that you startcooling, then you stop it to transfer the patients to the ER, tothe CATH lab to put in catheters. All this time they are havingups and downs of temperature that may cause harm. If we canfind a way to prehospital cool more gradually and more ef-fectively, perhaps it would be beneficial. I guess, the questionis, are we having arrhythmias because the patient’s temper-ature is going up and down? Also, in the brain, is there aproblem with going up and down with the temperature in thecomatose patient?

Dr. Justin Lundbye: I think Dalton can probably speak a lotmore on this, but clearly there is a huge concern of having thepatient fluctuate in temperature and even become febrile,which worsens outcome in all of these patients. There aresome data on temperature management in keeping them assteady as possible even in the clinical arena. As far as fi-brillating and arrhythmias, you don’t tend to see that aroundthe temperatures we’re dealing with in the 32–31� range.Fibrillation tends to occur a little bit lower than that (e.g.,29�C), and I think that’s why we try to stay away from thattemperature when we start.

Dr. Dalton Dietrich: In the spinal cord–injured populations,they are already having some autonomic problems, so we tryto maintain the temperature above 33� because with cooling,the heart rate does start slowing down. That’s why we keep itabove 33�C.

Comment: I’d like to make a comment about the prehospitalquestion, although I’m going to address this in greater detailtomorrow. One of the issues we face in our communityhospital is that we cover a very large area of 2200 squaremiles. We do use prehospital iced saline, but we’ve devel-oped a system in which you can use topical, intravascular, orwhatever cooling method you want. It’s rapidly applied, andtreatment is carried through the ED, the cath lab, and the ICUby basically plugging and unplugging the blankets on and offthe machines since we have multiple machines and systemsin each of these places. We’ve systemized it, just for the exactissue you brought up regarding the potential variations intemperature. This is one of our concerns from the beginning.We’ve tried to come up with ways to address this.

Question: A question for Dr. Lundbye is that, in the non-shockable rhythm group, are we doing sufficient service tothe ideology of the underlying mechanisms by which the

PEA or asystolic event occurred? The observation is this:The patients with chronic hypoxic, hyperventilation whohave an out-of-hospital chronic respiratory failure arrestand their resuscitation rhythm is a PEA systolic rhythm,they come in—and this is purely anecdotal—you have themstabilized and cool them, and they tend to have a betteroutcome than even many of our primarily cardiac arrestpatients. The contrasting observation is the patient who hasa true obstructive shock pattern, that is, massive pulmonaryembolism. The patient’s PEA arrest rhythm is primarilycardiovascular injury. There is an absolutely shockingdown time and really no hypoxic tolerance. That reallychallenges the question of whether dumping all those pa-tients into one basket gives us a sufficient understandingabout pathogenesis and outcome.

Dr. Justin Lundbye: I know you are absolutely right, and Ithink that based on the reports we have come up with, most ofour patients are the former, which is the hypoxic-driven slowarrest, and the more sudden PEA arrests are less common inour data and probably elsewhere too. It is a fascinating con-cept, the whole idea of preconditioning—you know, someonewho is chronically hypoxic and how they fare as compared tothe ones that go down without any type of preconditioning.We haven’t looked at them but I would be very curious.

Question: First off, I was just a little confused with theHOPES trial and the cooling protocol for TBI. As everyanesthesia care provider wants to know, exactly what timeframe are we looking at? On your slide it said cool for 72hours, and then on our handout slides it said cool for 48hours. Then you were saying that we would have to throwout any evidence in which any temperature was greater than35�C when the hematoma was removed. So I’m just kind oftrying to look at a time frame and really understand it.

Dr. Ross Bullock: Right. We went back and forth severaltimes, and I apologize for that confusion. The entry time ofthe study for onset of hypothermia has to be within 6 hours ofinjury—within 6 hours of trauma. So that’s quite difficult.The duration of hypothermia is 72 hours, but the way theprotocol is written, if intracranial pressure remains high forlonger than the 72 hours, then the treating physician has theoption to keep the hypothermia on longer, providing that theintracranial pressure is high.

Dr. Dalton Dietrich: I think that is something that KeesPolderman talked about last year. Our previous hypothermiatrials targeting TBI actually were normalizing temperature ata time when brain edema was still elevated. It just didn’tmake any sense at that time to normalize. So I think we’velearned from those early studies to be a little bit more flexiblein terms of what the patient is doing and the rewarmingprotocols.

Dr. Ross Bullock: Yes, there is a slow rewarming phase builtin, but that is included in the 72 hours. So that might explainsome of that discrepancy between 48 and 72. It is a third of adegree for our rewarming rate. That is the maximum rate.You can go slower with the way the protocol is written. But Ithink Dalton is absolutely right about the current speculationbeing that the reason Dr. Clifton’s trial and the Japanese

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hypothermia trial may have failed is that their duration ofhypothermia was maybe too short, and rewarming could havebeen too rapid—as brief as 24 hours in some of those trials.

Question: In our laboratory, we saw very, very bad resultswith cardiac tamponade. We then changed our policy fromCPR to the airway, breathing and circulation (ABC) to seefirst. So our first effort when we see the cardiac tamponade isto relieve the tamponade. After we changed to this policy, wehad a 33% increase in survival of those cardiac tamponadepatients. Do you know if you have the same experience?

Dr. Justin Lundbye: We haven’t looked at that, but it isfascinating. A lot of the therapy and the improvements wereactually just from the way you resuscitated the patient and notfrom downstream therapy. We have not looked at it. We don’tgenerally see a lot of these obstructive cardiac arrest patients.It’s not that common in our PEA patient population; it’smaybe seen more in the hypoxia-driven cardiac arrest cases.

Comment: Well, we have the same. We see hypoxia derivingfrom, for example, attempted suicide by hanging. Maybe youbetter not start with cooling them because they all die.

Dr. Justin Lundbye: There have only been a few case re-ports that have been successes, but most of them do very, verypoorly. I think there is one report maybe last year where theytalked about a pretty good success story in the hangingpopulation, but that’s it.

Dr. Dalton Dietrich: I’m interested in identifying bio-markers to help us decide just how cool a patient should be orhow long we should cool a patient. Ross mentioned bloodbiomarker assessment in the reperfusion injury state. Doesanybody have biomarkers they are using to target injury thatmay be temperature sensitive and may help devise strategiesfor trials, targeting a variety of human disorders?

Comment: David Erlinge from Sweden. We have publishedjust a few weeks ago a critical care study on microRNAs aftercardiac arrest. We have found one that has very strongprognostic information, which is microRNA 124. It’s quitegood at prognosticating what will happen for the patient inthe future. I think it discriminates a little bit earlier, maybe bythe first day, what will happen to the patient. If that can helpguide the choice of hypothermia, I don’t know. But it is oneinteresting new biomarker to look at.

Question: I have two questions. The first question is about aspinal cord–injured patient. Some patients are hypothermicautomatically after injury. So do you think for those kindsof patients applying therapeutic hypothermia will be stillprotective?

Dr. Dalton Dietrich: As with the TBI, some patients come tothe emergency room hypothermic. In those patients, hypo-thermia would not be introduced. In fact, the exact oppositestrategy may be initiated depending on the level of hypo-thermia. In patients with profound hypothermia, for example,an attempt to gradually bring temperature up to normother-mia, or whatever level would maximize good outcome,would be attempted.

Dr. Ross Bullock: Yes, within the context of TBI, there wereseveral studies done in 2006 on this topic, and the results wereconflicting. If you measure brain temperature as was done inthose studies, one found that of those patients who come inwith a cool brain temperature below 35, almost all die. Thereason for that is that there is almost no brain perfusion in theworst TBI cases and they were on their way to brain death. Soin our own series, we studied probably 80–90 patients thatway, and we found that most of those who had brain tem-peratures under 35�C died. So that is kind of counterintuitive;it’s hard to explain except that they had the most severe braininjury.

Dr. Dalton Dietrich: So if you relate that approach to SCI,many times the patient does not have a pure SCI. They couldalso have brain injury or multiorgan trauma. In those types ofscenarios if the patient was profoundly hypothermic, youwould try to introduce a targeted temperature managementprotocol that would be best for that particular subject.

Dr. Ross Bullock: And just to take that further, what weshowed was that the brain–body temperature gradient wasimportant. If the brain–body gradient was negative, in otherwords, the brain was cooler than the body, almost all thosepatients did extremely badly. Because normally in TBI, thebrain is warmer than the body. The study showed that thosebrain hyperthermia patients are the ones that might benefitfrom cooling. Where the brain–body gradient was neutral,those patients did well too.

Question: My second question involves the duration ofhypothermia, for 48 or 72 hours, followed by the rewarmingperiod. Did you observe refractory hyperthermia in thosebrain trauma or spinal cord–injured patients?

Dr. Dalton Dietrich: In SCI, some of the subjects do haverefractive hyperthermia days after the injury. We use severalstrategies, including both external and internal cooling ap-proaches. So while they are in the ICU, we do everything wecan to at least normalize temperature. But yes, spinal cord–injured subjects have infections and pneumonias, and theytend to have periods of hyperthermia. Even during the re-habilitation period, there is a new study showing hyper-thermia in SCI patients many weeks out after injury becauseof limitation in thermal control. I think Pat’s point earlierabout preclinical work being restricted to young healthyanimals is important. The stroke field is doing a good jobwhere they actually include different types of comorbiditiesthat are relevant to the patient population, including age,hypertension, and diabetes. That is making a big differencein terms of reevaluating therapies. In SCI we tend to em-phasize that they are relatively young males. But now, theaverage age for SCI is 44 in the United States. Slowly thatage is increasing, and aging with SCI and the age at whichyou have the SCI are being discussed more in terms of thechronic care phase.

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Yokobori S, Gajavelli S, Mondello S, Mo-Seaney J, BramlettHM, Dietrich WD, Bullock MR. Neuroprotective effect ofpreoperatively induced mild hypothermia as determined bybiomarkers and histopathological estimation in a rat subduralhematoma decompression model. J. Neurosurg. 2013;118:370–380.

Yokobori S, Zhang Z, Moghieb A, Mondello S, Gajavelli S,Dietrich WD, Bramlett H, Hayes RL, Wang M, Wang KK,Bullock MR. Acute diagnostic biomarkers for spinal cordinjury: review of the literature and preliminary research re-port. World Neurosurg. 2013. pii: S1878-8750(13)00459–2.[Epub ahead of print]

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