Hi. I’m Pat Kochanek. I’m the Grenvik Professor of Critical Careat the University of Pittsburgh and lead author of the guidelines for the management of severetraumatic brain injury in children. In today’s presentation, we’ll talk aboutthe three exciting new guidelines documents, the full guidelines, the executive summary,and the new algorithm articles that are published in the March issue of Pediatric Critical Care. Welcome. This is World Shared Practice Forum. My name’s Robert Tasker. I’m the Director of Neurocritical Care. And today, I have Dr. Pat Kochanek with me,who is the Ake Grenvik Professor of Critical Care Medicine at the University of Pittsburgh. He’s also the Director of Research at theSafar Institute. And most importantly, you’ll all know himas the editor-in-chief of Pediatric Critical Care Medicine. And in 2017, he was the Thomson Reuters ScienceWatch most prolific writer with most citations in the field of traumatic brain injury research. Today, Pat is here to talk to us about thenew third edition update for the Brain Trauma Foundation guidelines in traumatic brain injurymanagement in children. So Pat, I’d just like to ask you, how didall of this come about? It’s a huge organizational achievement, buthow did it start, and how did you get here? It’s a great question. And thanks for the kind introduction. The guidelines have been a process that, asyou know now with the third edition, are one that brings together a really multidisciplinarygroup of people. Not only intensivists and neurosurgeons, emergencymedicine, anesthesia, child neurology, et cetera, but also evidence-based medicine experts,and obviously all the people required to do all the publishing. And it’s a process that many people may notknow that, a couple decades ago, this was tried and failed, initially, by other groups. And in large part, Nancy Carney and the OrganHealth Sciences Group, with the Brain Trauma Foundation, kind of assembled a group of peoplewith the first edition of the guidelines that were able to finally take it to the finishline. And now, the third edition has really cometogether. And although it’s a huge undertaking, it’sso much easier than it was in the beginning. And beyond the actual people whose names yousee on the masthead of the documents, there are other people. Hector Wong, for instance, served as the guesteditor to, in essence, address any potential conflicts. And he brought on reviewers to review. And so there was a huge cast. But as I mentioned, I think it was a lot easierthis time than it was particularly the first time. Thank you. So why have we got three documents this time? Talk us through that. I think it’s really great, first of all–that’s my initial reaction– the fact that we have three documents. In fact, if you look back at the greatestcritique of the last edition of the guidelines was that there wasn’t a bedside handbook,an algorithm type of document. And I think that, if you look back at theguidelines, we have three documents now. You can see that we have the full guidelines. And the full guidelines, of course, are essentiallythe bible. But they have everything in them. But we then also, this time, have publishednow, rather than as a supplement, in the regular pages of Pediatric Critical Care Medicine,and dually published in the regular pages of the journal Neurosurgery, we have an executivesummary. And that executive summary is a thumbnailof the essence of what has changed, that there are 22 recommendations and there are ninenew recommendations.
are 22 recommendations and there are ninenew recommendations. And so that is really a distilled, easy-to-readversion. And if nothing else, I suggest you read thetables of that document. And then, this time, we did something thatwe did in a very spartan way in the first version of the guidelines. And that is tried to put together a bedsidecaregivers document, an algorithm that isn’t just evidence-based, that is consensus andevidence-based. And if you were to go back to the last guidelines,the number one, if you want to call it, complaint of people was, where’s the algorithm? Where is my bedside document that I can lookat? Are there a couple of charts that can helpguide me through? You can argue why wasn’t there one in thelast document. And that’s an interesting point. And the reason there wasn’t one is that, inthat era, the Brain Trauma Foundation was in, if you want to call it, kind of a puristera. They wanted to minimize consensus. They wanted evidence. And so an algorithm was, in essence, not soughtout. And I think hearing all of the feedback thatwe really need something like this, because the evidence is better, but it’s still notsolid enough. And so this algorithm article, I think, isa fantastic addition. We’ll talk a little bit more about it later,but it’s a really special addition. So that’s why there are three documents. Really, from a logistics standpoint, if youread the executive summary and use the algorithm and have the full document as kind of yourbackup if you need to really go into the details, I think that’s the best way to navigate thethree. Can I just interrupt? Yes, yes. So all of the previous recommendations andlevels of evidence were relating to the outcome of death or mortality. Here, now, we’ve introduced a different outcomelevel, which is ICP control. Perhaps you could just talk us through that. That’s a great point. And it’s a very interesting point in that,really, there’s been no definitive positive study that has ever shown that an interventionimproves outcome in severe TBI in children. And you’ll see in minute we’ve certainly hadone that has at least a level three evidence, if I remember correctly, supporting against. And I guess we’ve got a couple of those. Outcome has been such a difficult parameter,whether it’s mortality or whether it’s Glasgow Outcome Scale, to get a therapy to favorablyaffect that, that the next best surrogate that we have, obviously, is intracranial pressure. And so we have two different types of targetsfor our recommendations. One is, is it useful for outcome, for improvingoverall outcome? And can we really make a recommendation inthat? And the other is, can we make a recommendationto control ICP? As you know, the evidence to definitivelysay that controlling ICP improves outcome is also just not solid enough. And so thus, the need for a dichotomy betweenthose two. Perfect. Thank you. So perhaps you could take us through the evidencetables that are summarized in the executive summary, just to highlight various aspectshere. Yeah. As I mentioned, there are 22 recommendations. And there are also some other notes withinthe tables. And they’re very useful. And there are nine new recommendations. And so if you look through the executive summarytables, you see that, for instance, the recommendations for monitoring, probably the hottest topicon the planet is ICP monitoring.
for monitoring, probably the hottest topicon the planet is ICP monitoring. And based on the available evidence, thereis a recommendation for the suggestion for ICP monitoring. It’s interesting that there is that recommendation,given the fact that almost everything that you do is based on using ICP monitoring. And we’ll talk a little bit later, I’m sure,about if you don’t use ICP monitoring, you’re still stuck with, in essence, ICP-based carewithout the number. So there is at least a level three recommendationfor that. There’s also, once again, a recommendationfor advanced neuro monitoring for PbrO2, partial pressure of brain oxygen, and with a Licoxmonitor. And it’s a parenchymal monitor, for thosewho aren’t familiar with it. And if you do use one, that you target a levelof above 10 millimeters of mercury. And that’s a threshold. We’ll talk a little bit about thresholds ingeneral later. It wasn’t felt that there was enough evidenceto support a recommendation for use of the monitor. It’s used more commonly in research institutions,et cetera. But if you do use it, that was the thresholdthat was recommended. And then there are two recommendations onneuroimaging. One, that a normal CT scan does not rule outincreased intracranial pressure. And I think that’s an important recommendation. And also, that routine repeat use of a CTscan is not recommended, unless, of course, there’s some clinical deterioration. And all of these are level three recommendations. All of these are level three, as you can see. Yes. And I’ll try to point out the three leveltwos with a little bit more clarity. Thank you. And then, with the thresholds, there are,again, level three recommendations for an intracranial pressure threshold of 20, tokeep it less than 20. And that is interesting because the latestadult guidelines had a 22 recommendation. It’s interesting also that, with this recommendation,I think like cerebral perfusion pressure, there may be an age-dependent value. It might be that, in an infant, 20 is a littlehigh. But we just don’t have the evidence to saymore. And the same as with cerebral perfusion pressure. We had a recommendation, once again, for aminimum of 40, but we also have a recommendation that 40 to 50 may be a more practical recommendation,given that we don’t want to breach that threshold of 40. And we also mentioned there may be age-specificthresholds specifically for CPP, given the well recognized age-dependence of blood pressureand the importance of blood pressure in the CPP calculation. But once again, we can’t make specific recommendations. I think one of the papers from your centerback in Cambridge, when you were there, was one of the best that came as close to givingus a shot at doing that, and maybe future studies will be able to pin that down a littlebetter. So for hypertonic saline now, we do have alevel two recommendation for bolus administration of 3%, and with specific doses, and I thinkthat that’s a nice advance in this guideline. I think the paper by Steve Shein, I think,really helped contribute to this because it was the first time that an actual comparisonbetween therapies– first tier types of therapies, whether it was hypertonic saline, or fentanyl,et cetera, provided evidence that the hypertonic saline not only improved ICP, but it alsowas the only therapy that improved CPP, and that was kind of an exciting finding fromthat. We also continue to have level three recommendationsfor a hypertonic saline as a continuous infusion, and that was in the prior guidelines. But now, in other new 23.4% hypertonic salinerecommendation based on studies from down under, I guess you would say. Really exciting to see. You, I’m sure, and maybe the audience isn’tas aware, but 23% is used much more commonly
head brain teaser You, I’m sure, and maybe the audience isn’tas aware, but 23% is used much more commonly
You, I’m sure, and maybe the audience isn’tas aware, but 23% is used much more commonly in the adult world. Interestingly, I think the pediatric field,largely related to the work out of San Diego, brought hypertonic saline back into the armamentariumwith 3%, and in the adult world, brought the 23% in, and now we have a 23% paper in pediatrics. So having that in your armamentarium. Just to make clear, we couldn’t find any studiesin regard to mannitol. It’s a really great point. And despite the history of mannitol use, I’mreally hopeful that ADAPT will now be able to– the ADAPT trial, led by Mike Bell, whichjust closed 1,000 patients– it’s a comparative effectiveness trial funded by the NINDS, andI’m really hopeful that is going to give us some insight into the effect of mannitol. Part of the reason we don’t have evidencefor mannitol is that some of the really early studies supporting its use were, in essence,accepted. And people didn’t feel the need to replicatethem, but the studies in that era just don’t hold up to the rigor of today’s type of reports. And so it’s a bit of a conundrum, and it’skind of a bummer, I guess you would say, but it doesn’t mean that we don’t recommend againstmannitol as an alternative to hypertonic saline. We just don’t have the evidence in the articlesto support its use. The other thing with regard to the hyperosmolartherapy is that, once again, we have some safety recommendations showing that sustainedincreases at high levels, and whether you pick 160 or 170, you start to see complications. And whether it’s evidence of an endotheliopathywith thrombocytopenia, and pulmonary complications, or whether you have thrombotic complications,it starts to come in. And so you get a trade for use at those higherlevels. Also we had some other new recommendationsthis time. Again, very exciting. A category that, I think, pediatrics has alsoled the way in initially. We were kind of the first people to put achapter in on sedation. We didn’t have much to say, but it has– Ithink it really stimulated some studies. This study out of Wash U showing that midazolamand fentanyl combined, in particular, was associated with not an improvement in ICPwhen used as a bolus, but actually some deleterious effects. So that was somewhat of a complicated study,but there were clearly some signals of a deleterious effect, allowing us to have a level threerecommendation against routine bolusing of those agents. I think it’s really important, though, torecognize that in that recommendation, that we are assuring that the patient, the kid,is already adequately sedated. So this is not to tie the hands of the caregiverto not sedate or provide appropriate analgesia to kids with severe TBI, but rather if youare already doing that, just coming in with additional boluses don’t seem to produce importantimprovements in ICP. Although, if you were to compare the studyfrom Wash U, Jose Pineda’s group, they saw, really, predominantly negative effects. In Steve Shein’s study, we saw some benefiton ICP, but no benefit on CPP. I think taken together, it really argued morefor give boluses of hypertonic saline or other therapies if you are adequately sedating. And then, of course, another very importantdifference between the adult guidelines and pediatric guidelines– in the adult world,propofol is, in a number of studies, been shown to be a very good way to provide sedationin neurocritical care of adults, but obviously, with a black box warning. It’s just not on the table in pediatrics. And although we don’t have a study in TBIsaying we can’t use it, you could argue there’s something at a higher level preventing theuse of it as a continuous sedation approach in pediatric TBI. I also wanted to mention that we don’t havea specific recommendation on neuromuscular blockade, but we do say that its use is upto the treating physician, and we deal with that a little bit more in the algorithm. We also have a number of other level threetreatment recommendations– cerebral spinal fluid drainage if you’re using a ventricularcatheter.
fluid drainage if you’re using a ventricularcatheter. Seizure prophylaxis, level three also, althoughwe didn’t have evidence to say levetiracetam, or fenotin, or fosphenytoin were better. Either was better. And then we also had a level three recommendationagainst prophylactic hyperventilation. However, if you have refractory intracranialhypertension, now kind of as a second tier hyperventilation can be used, and there isa level three recommendation for it. And once again, I think that becomes a littleclearer on the algorithm. It’s kind of like what you use upfront versushey, we’re not winning, now what are the choices I have, I guess would be the way I would putit. I think one of the greatest improvements innot necessarily as much related to the new data as much as related to the interpretationof it, has come with the temperature control, and we now have a level two recommendation. And now this, as you are talking, this iswith overall outcome, as was the early hyperventilation. Not for ICP control, but for overall outcome–a recommendation against prophylactic hypothermia. So if a patient comes in, you just immediatelycool them in kind of a neuro-protective fashion, and despite how wonderful that sounds, anddespite many animal studies suggesting that there was some potential for that, it’s justnever panned out. Although, we still don’t have, in essence,perfect studies on that. There are some signals that during re-warming,you might run into some difficulties, and I always say hypothermia is not a pill. It’s complicated. And so in those studies, if anything, therewere some trends in some of them for deleterious effects, and so we have a level two recommendationagainst doing that. However, for ICP control, once again, if yourfirst line therapies are failing, moderate hypothermia to attenuate intracranial hypertensionis on the table. So it’s like a differentiation between whatyou would do first tier, and then what you would do second tier. Exactly. A preventative strike with mild cooling isnot recommended. In fact, we recommend against it. Whereas if the conventional first line therapiesare failing, hey, this is something that is– there is evidence to say that it can controlICP, and that’s a very different situation than upfront application. And similarly, for refractory intracranialhypertension, we have level three recommendations, once again, for barbiturates, and for decompressingcraniotomy. And those are, basically, the same. There was a little bit more evidence supportingthem, but still, all at level three. I mean, perhaps, it’s also worth just mentioningthat we did have pediatric neurosurgeons review all of the evidence on the decompressing craniotomyliterature to go through that in really quite some detail as well. Oh, yes. That was something that, I think, in all threeguidelines, we have been very, very mindful to be inclusive on the team, and I think thateveryone felt comfortable with every recommendation. I think there really was a consensus on theevidence portion. I think there was an excellent consensus evenon the algorithm, but there was strong agreement. And even recognizing that some centers usedecompressive craniotomy in a more prophylactic way. But I think the evidence that we can statein the guidelines are the use of it for a refractory intracranial hypertension. Or in a neurologic deterioration, et cetera,it could be that you would use it upfront if you had a terrible injury with a largeparenchymal lesion, et cetera, but it is in that context. And then the final two areas in the treatment,one is in nutrition, and there is a level two recommendation that, once again, is inthe guidelines. It’s a really excellent study, but it’s astudy on a very specific immune modulating diet, and the study was well conducted, andthus, enough to give it level two recommendation. But beyond that, if we’re not using that diet,it doesn’t help us very much because it was so specific. It’s an excellent study, but it’s difficultto generalize beyond it. In contrast, we now have another new recommendationto start nutrition within 72 hours. That approach has even stronger evidence subsequentto the guidelines. Again, and that’s for improving overall outcome. It’s a level three recommendation, but itdid not differentiate whether you– exactly what kind of rate of enteral nutrition orexactly what the recipe was, but I think it’s still a first step forward on that. And then finally, interestingly, the recommendationon corticosteroid use moved from a level two against to a level three against. And people may not realize this, that we’rehumans putting together these guidelines. And the backdrop upon which they are craftedchanges with time. This, to me, is a really interesting examplethat earlier on when the CRASH trial came out, it was a study of steroids in adultswith thousands of patients– negative, deleterious. It influenced the field like a hammer, andI think that that study probably was given too much weight by us in the past. And as we’ve looked more rigorously and saidto ourself, but where’s the pediatric evidence? We have said– and maybe part of it is well,we’ve gotten some better pediatric evidence for other pieces of this. So that study, even though it’s, I think,a level one in the adult guidelines, it’s not a pediatric study, and so we can’t justsimply extrapolate. And the pediatric evidence is really levelthree against corticosteroids. And the other thing I think that we are tryingto be very mindful of is that we don’t want to tie the hands of our caregivers to notbe able to use steroids in the setting of adrenal suppression. And whether it’s etomidate, or whether it’sprior steroid use, or other problems– HPA axis. Sure, HPA axis injury. Absolutely. So I think in that setting, we moved thatfrom a level two to a level three. That’s one of the more interesting nuances,I think. If you weren’t really looking carefully atthe guidelines, you wouldn’t have thought that changed, but it’s an interesting thing. That’s a great summary, Pat. And you sort of alluded to it when you mentionedthat there have been other studies coming out since this was all written. And the question is do we have to wait anotherfive or six years before the next set of guidelines? Or is there going to be a completely differentstrategy with dealing with new evidence as it comes out? It’s a great idea. Living guidelines is something that has beendiscussed. I think that there is interest from the BrainTrauma Foundation of doing that. It’s not easy, though. It takes a lot of work. And I think that it probably takes a certainlevel of financial support too. And so exactly whether that will come together,I don’t know. I really don’t. I think it’s a great idea. I think the other question is a living guidelinekind of is so logical now. Everyone just goes to their phone for whathappened last night. I think that is certainly where it’s goingto go. I think it’s interesting that we’re almostin a scenario where the mechanics to make that happen in the transition need to be workedout. And I hope it does happen, but I do thinkthat it’s not a trivial undertaking to do. That’s how I would describe it. I would think if we could update at leastevery year or two years, that would be even a step that probably is going to be necessary,because otherwise, these become outdated pretty quickly. Thank you, Pat. That was really clear. And now, it comes to the bedside documentor the algorithm. Perhaps, you could just sort of talk us throughthe concept and the figures that appear there. Yeah, as I mentioned a little earlier, withthe first guidelines, there was an algorithm. At that point in time, we felt it was reallyimportant. That initial algorithm in that first document,though, was really a synthesis of the evidence into an algorithm with a little bit of consensus. It was still a very largely evidence drivendocument. As I mentioned, the Brain Trauma Foundationwith a second edition really pushed for “We need pure evidence”, and kind of almost a religiouskind of approach. And this time around, I think it just becameso clear from the feedback that we received that people want more than that. And so we put together– and I’m really pleasedto say that the two of us together are the co-lead authors of this, and it’s a fantasticthing. I think it’s one of the best things I’ve everbeen part of in my career. That tried to really build a much strongerconsensus layered upon the evidence, and address some issues that are really neglected, andit was really fun– even discussing this at the guidelines committee, we had great people. Marc Wainwright, and Mike Bell, and–Dave Adelson. Dave Adelson, and Monica Vavilala, Nate Selden. And everyone was weighing in on this, andthings like– TBI is this multifaceted disease, where you have ICP, CPP, brain tissue O2,all these different readouts, simultaneously, and each of them is their own linear pathway,but they influence each other, and there’s never any discussion of those in kind of asterile guidelines document. Or things like the tempo. I always chuckle because when we were talking,Mike Bell had a great comment. He said you have a guidelines, and you havea level one pathway, and you say well, in one patient they blow through this in 15 minutes. In another patient, it’s like they behave,and they follow it, and their ICP raises over several days, and you can just nicelyimplement the therapy. But you’re stuck with the same sterile guideline. You know, things like weaning. You can read through all the guidelines, andno one ever says, well, is there anything about weaning? How do you take the therapies off? We all do it in our own way, and we all, generally,take the most toxic and the last thing on as the first thing off, et cetera, but noone ever discusses it. You just don’t find it in a document. And another point in the algorithm that Ithink is really important– and this became– we discussed this– I think we were really excited when we starteddiscussing this in that thresholds that are generated in guidelines document are the minimumthreshold. And the classic, obviously, is a CPP of 40,and we say, man, that’s low. And if you’re targeting 40, you’re going tobe in the 30s some time period. And we’re going, wow, but you’re stuck withthat. And so the algorithm article discusses, Ithink, really nicely that these thresholds are minimum targets. And whether it’s a hemoglobin of seven, oran ICP of 20, or a CPP of 40, or a brain tissue O2 of 10. Heck, you can find articles that say we shoulduse 25 or 30 as the target, but the strongest evidence, the most cautious, of course, is10. And you might argue, well, why not just raisethose empirically? But more therapy might also get you into trouble. And so running something too rich– I mean,look at with fluid overload now. It used to be– I always used to say, pourit like you don’t own it. But now, we are all saying hey, there is a price to pay for these things that we do in the ICU. And so the concept of a minimum thresholdis one that we discuss in the algorithm. We would like, now, to turn to the audienceto ask a question. When you respond, please leave your city andcountry. What did you find most helpful about the threenew guidelines documents? I think we’re really pleased that it’s nice,visually, to look at. You see the linear pathways. You see the potential interaction. The first tier algorithm, which is, I think,a really nice graphical display, builds on the baseline care. And these kind of things, if you look backat the prior guidelines, in the introductory article, were kind of a brief discussion,but they weren’t really laid out for the bedside caregiver. And I think this time, for the first time,we’ve really laid them out and said, here’s a strawman to utilize. And going back to Mike Bell’s analogy, youmight have a patient that blows through this in a few hours, and then you might have anotherpatient that never progresses to second tier therapy. Some utilization of this allows you to doall of your management. I think one of the other things about thisthat I always personally felt we fell short in the prior guidelines is herniation is sodevastating. It’s just so important, and yet there areno studies on it. Even in the adult side, there are only a fewstudies on herniation. It’s really interesting if you look at thoseadult studies. And you mean what would you would do in anemergency? That’s right. And not only what you would do, but what arethe consequences? It’s not like well, we’re going to randomizeto A or B in herniation. That’s a little tricky. And not to say that it couldn’t be done totry to improve what our best approach is on that, but I think one of the things– if youlook at some of the– I think there’s about three adult studies on herniation– the interestingthing is that there is a pretty decent number of patients that herniation can be reversed. We think of it as it’s so devastating, andrightfully so, but it’s not always. And the early signs and symptoms in some patientscan be reversed, and it may be 40% or 50%. And so that’s really important. All the more reason to have a recipe. And so we have what I called the herniationpathway, and it has a nice backdrop on, well, what are the signs and symptoms because itvaries from patient to patient, obviously. And then how do you manage it? And that is the setting that hyperventilation,titrating to pupillary, reversal of pupillary dilation is indicated. And on an FiO2 of 1.0, and then bolus mannitolor hypertonic saline. It’s interesting, in the adult studies, it’susually 23.4% saline, but I think in pediatrics, people still– the guidelines committee feltthat in this setting, more people are comfortable with mannitol. And what we didn’t want to do was to try tointroduce something new in that crisis setting that people are trying to find something thatthey’re not prepared for. Maybe that will ultimately evolve, but thatwasn’t the goal of this. And then, of course, if you have an EVD inplace, to open it, and make sure you’re maximally draining CSF. And then get to–Imaging and surgery. Of course. And so having that kind of crystallized onthere, if it saved one or two kids, it was a great addition to these. And then as I mentioned, within this, we havea nice discussion about an ICP pathway, and how do you progress down it. And the CPP pathway– what do you do to addto this? And then the brain tissue O2 pathway. And one of the things that’s always broughtup, well, how does one influence another? And the classic example I think that is reallya nice one is that if you were in a unit, and you’re monitoring all three of these,and you have a situation where the ICP is under control, and the CPP is under control,and your ICP, say, is 16, and you’re on osmolar therapy, and it’s taken barbiturates to getto that. But now you have a patient whose brain tissueO2 levels are low. Say, they’re seven or eight. And you’re saying, well, our ICP is undercontrol, but our brain tissue O2 is inadequate. Should we just be satisfied with that? A classic example is to say, well, let’s letthe pCO2 rise a little bit. Or let’s raise our blood pressure a littlebit. Hemoglobin. Transfuse. Yes, do an intervention that will maybe improvebrain tissue O2. So now, all your targets are adequately addressed,even recognizing we don’t know exactly what the best value is. But the range of targets for each of these,and references to the individual protocols that people use, are all in the algorithmpapers as well. Yes, absolutely. And then, of course, once you get beyond this,you, of course, have refractory intracranial hypertension, and another tier. And you could argue, well, is it artificialto really consider this a tier, et cetera? I think maybe in the past, we might have thoughtto some extent that’s the case, but now, I think you can see it from the new guidelines,by having level two evidence for hyperosmolar therapy, it kind of opened the door to reallymore definitively say yes, that’s level two evidence, and that’s a therapy that, in general,until you get to high levels of sodium, is probably reasonably safe. And now you get to therapies that are muchmore risky. And so if you’re not controlling ICP withthat first tier of therapies, you have choices. And as I mentioned, barbiturates, moderatehypothermia, hyperventilation, and pushing osoms. I like the way this is presented, now, becauseit’s not linear. We don’t know what order to do these things. Would you do barbiturates and then hypothermia? Or hypothermia, then barbiturates? Or the hyperventilation? Have you got a comment about that? Yeah, it’s a really great point. We not only don’t know what order that thisshould be first, and this should be second, but we also don’t know because, commonly,you need more than one of these. We all have tons of patients where, hey, we’vehad to go to barbiturates and push a hyperosmolar therapy to 165, or whatever. Or push ventilation. Or, hey, we have to cool. So what combination? Not only what order, but is there a combination? And I think two things come to mind with me,and that is that combinations are common, and we don’t know which one’s better. But also, it may be that either individualuse or combination use, the efficacy depends on the center because I think that these kindof advanced therapies, they take skill. They really do. You start barbiturates, you better be readyto support hemodynamics. I remember Brad Peterson from San Diego sayingI would never allow the blood pressure to be low if I started of a barbiturate infusion. With that kind of mindset that you don’t startit and wait for trouble, you are all over it. You’ve got the presser, essentially, teedup to the patient at the time you start it. And there may be some centers that are greatat decompression, and they want to go to decompression at that point. Obviously, the evidence, even on the adultside, pretty equivocal on that also. So I do think this may vary, depending onthe center. And I think the other thing is that this wholeguidelines, the backdrop of it, is as if we are dealing with one disease. And we know now that it’s very likely thatthe phenotypes of TBI are going to be important, and it may be that particularly for somethinglike second tier therapies, that one type of second tier therapy is way more effective,say, if you have someone with diffuse axonal injury, and diffuse swelling, that may bevery different than someone who had a big subdural, and has a focal lesion, or a bigcontusion. And so ultimately, this will evolve to somethingmuch more elegant. We would like to turn again to our audienceto ask a question. When you respond, please leave your city andcountry location. What do you think might be changed to improvethe value of future guidelines to caregivers? And the other component of this, if we’regoing to go to these advanced therapies in the second tier, we’ve also got a sectionon advanced neuro-monitoring. And there wasn’t a great deal of evidencein the main document to support these– like EEG, transcranial Doppler, so-called PRX,et cetera. So have you got a comment about that component? If you look carefully at the algorithm document,we do make some comments even on the first tier to say that, for instance, if you useneuromuscular blockade, we strongly suggest using continuous EEG. And obviously, once you start to get intothese more second tier therapies, advanced monitoring, I think, can be very helpful. As you say, we don’t really have great evidence. I’m one of the people that believes that it’snice to have advanced monitoring as much as you can from the word go. Recognizing that you don’t overreact to anyone monitor. I really think that as with therapies, I’ma believer in a little of a lot of therapies, rather than a lot of one therapy. That’s where I’ve seen people get into troubleis almost being a zealot about one approach, and pushing it, really, and I think that wesee in all of these therapies that the toxicities are dose-dependent. And so if you can use a little of a lot oftherapies, almost like an artist, you can– and with many advanced monitors, I think thatthat’s one of the ways that you can optimize outcome. I don’t think we’re there yet in a guidelineor an algorithm, and I’m just saying that kind of off the cuff. It’s a wish for the future. But I do think there is something to that. There’s, perhaps, one area that I just wantto pull you back on, and sort of garner your thoughts on, that’s the question of what ifwe haven’t got invasive ICP monitoring? What do we do? I think that is, really, a burning hot questionright now. That was really set into motion by Randy Chestnut’sbest trip study published in the New England Journal a few years back. And then more recently, Tellen Bennett’s JAMAPediatrics paper, and questioning whether this is, really, the key target that we shouldbe aiming for. And I think it’s so interesting because we’rereally excited that we actually do have a section in the algorithm article about thisquestion. And the real gap, though, is that if you don’tuse ICP monitoring, that there is no pediatric, not only data, there isn’t even a consensusor single center description of how you should manage it. And in Tellen’s paper, which wasn’t a studyof how to do it, it was just the way some people are managing what’s happening– whatare the consequences? Can we use statistics to try to sort thisout? And in that paper that questioned it, therewas no protocol. There were some percentages of what percentageof people use barbiturates, and what percentage of people– so A, we don’t really even havea document in pediatrics. But we do have Randy Chestnut in the supplementto that article in the New England Journal if you go in there, and they, of course, titrated. And they recruited over 12-year-olds, I think,in that study. Yes. Yes, that’s right. They titrated to clinical exam and imaging. I think that if you look at the results ofthat paper, there’s some truly fascinating results. One is that in many cases, the amount of therapythat was used was greater than if you used ICP monitoring. It kind of makes sense that if you just haveto guess at what kind of brain swelling there is, that you’re going to need to overshootbecause if you run it too thin, then you could get into trouble. And so, obviously, using those metrics– exactlyhow often you were to scan, et cetera– is totally unclear. But if you were to use those kind of metric,you would use the therapies that we have developed based on ICP monitoring, and then just haveto empirically implement them, and write your own protocol as to how you want to do it,or try to use the Randy Chestnut protocol in a pediatric analog of it. But you would have no evidence other thanthe evidence based on ICP. So you can’t get around the ICP influenceon it. I do think there’s one other take home point,though, from those studies, and that is I really believe that it may get back to thephenotyping. That we have underutilized imaging to helpus guide our treatment. Not so much we don’t get enough imaging, butwe, in general, have gotten imaging to say oh, they need to go to surgery, rather thanwow, there’s still a lot of swelling there. This brain looks tight. It’s almost like getting a compliance readout,instead of just an ICP readout, and saying, hey, we’re going to need therapy for a longerperiod of time. And I don’t think we’ve really– we haven’t,in any way, skimmed the surface even of how we might use imaging. And if we could get bedside MR, for instance,and perfusion MR, and things like that, I think it could really help influence our care. So I don’t have an answer for the no ICP otherthan if that is the approach, you need to craft a protocol based on the Chestnut study,and we really need the results of those kind of things, if that is what you’re doing, tobe published. And remarkably, it seems like the number ofcenters that don’t use ICP monitoring– or use them in selected patients– is prettysubstantial. The other thing that I would say about thatis the ADAPT trial isn’t going to provide us any information about that because, obviously,in that trial, ICP monitoring was an entry criteria. So that still will be a gap, even if adaptgives us some clues as to how to better manage. I’m hoping that based on adapt and the otherstudies, that we actually become better at utilizing and treating ICP, and that it willlead to better outcomes, rather than trying to take a step back and fly blind, I guesswould be how I would put it. Thank you very much, Pat. It’s been a real pleasure to speak with you,and talk about the guidelines documents. It’s a huge and massive achievement. Thank you. Thank you, and it’s in the March issue ofPCCM.