“Guidelines for the Management of Pediatric Severe Traumatic Brain Injury” by Pat Kochanek

By Adem Lewis / in , , , , , , , , , , , , , , , , , , , , , , , , /

Hi. I’m Pat Kochanek. I’m the Grenvik Professor of Critical Care
at the University of Pittsburgh and lead author of the guidelines for the management of severe
traumatic brain injury in children. In today’s presentation, we’ll talk about
the 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 the
Safar Institute. And most importantly, you’ll all know him
as the editor-in-chief of Pediatric Critical Care Medicine. And in 2017, he was the Thomson Reuters Science
Watch most prolific writer with most citations in the field of traumatic brain injury research. Today, Pat is here to talk to us about the
new third edition update for the Brain Trauma Foundation guidelines in traumatic brain injury
management in children. So Pat, I’d just like to ask you, how did
all of this come about? It’s a huge organizational achievement, but
how 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, as
you know now with the third edition, are one that brings together a really multidisciplinary
group of people. Not only intensivists and neurosurgeons, emergency
medicine, 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 not
know that, a couple decades ago, this was tried and failed, initially, by other groups. And in large part, Nancy Carney and the Organ
Health Sciences Group, with the Brain Trauma Foundation, kind of assembled a group of people
with the first edition of the guidelines that were able to finally take it to the finish
line. And now, the third edition has really come
together. And although it’s a huge undertaking, it’s
so much easier than it was in the beginning. And beyond the actual people whose names you
see on the masthead of the documents, there are other people. Hector Wong, for instance, served as the guest
editor 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 easier
this 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 greatest
critique 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 the
guidelines, we have three documents now. You can see that we have the full guidelines. And the full guidelines, of course, are essentially
the bible. But they have everything in them. But we then also, this time, have published
now, 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 executive
summary. And that executive summary is a thumbnail
of the essence of what has changed, that there are 22 recommendations and there are nine
new recommendations. And so that is really a distilled, easy-to-read
version. And if nothing else, I suggest you read the
tables of that document. And then, this time, we did something that
we did in a very spartan way in the first version of the guidelines. And that is tried to put together a bedside
caregivers document, an algorithm that isn’t just evidence-based, that is consensus and
evidence-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 look
at? Are there a couple of charts that can help
guide me through? You can argue why wasn’t there one in the
last document. And that’s an interesting point. And the reason there wasn’t one is that, in
that era, the Brain Trauma Foundation was in, if you want to call it, kind of a purist
era. They wanted to minimize consensus. They wanted evidence. And so an algorithm was, in essence, not sought
out. And I think hearing all of the feedback that
we really need something like this, because the evidence is better, but it’s still not
solid enough. And so this algorithm article, I think, is
a 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 you
read the executive summary and use the algorithm and have the full document as kind of your
backup if you need to really go into the details, I think that’s the best way to navigate the
three. Can I just interrupt? Yes, yes. So all of the previous recommendations and
levels of evidence were relating to the outcome of death or mortality. Here, now, we’ve introduced a different outcome
level, 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 intervention
improves outcome in severe TBI in children. And you’ll see in minute we’ve certainly had
one 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 favorably
affect that, that the next best surrogate that we have, obviously, is intracranial pressure. And so we have two different types of targets
for our recommendations. One is, is it useful for outcome, for improving
overall outcome? And can we really make a recommendation in
that? And the other is, can we make a recommendation
to control ICP? As you know, the evidence to definitively
say that controlling ICP improves outcome is also just not solid enough. And so thus, the need for a dichotomy between
those two. Perfect. Thank you. So perhaps you could take us through the evidence
tables that are summarized in the executive summary, just to highlight various aspects
here. Yeah. As I mentioned, there are 22 recommendations. And there are also some other notes within
the tables. And they’re very useful. And there are nine new recommendations. And so if you look through the executive summary
tables, you see that, for instance, the recommendations for monitoring, probably the hottest topic
on the planet is ICP monitoring. And based on the available evidence, there
is 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 care
without the number. So there is at least a level three recommendation
for that. There’s also, once again, a recommendation
for advanced neuro monitoring for PbrO2, partial pressure of brain oxygen, and with a Licox
monitor. And it’s a parenchymal monitor, for those
who aren’t familiar with it. And if you do use one, that you target a level
of above 10 millimeters of mercury. And that’s a threshold. We’ll talk a little bit about thresholds in
general later. It wasn’t felt that there was enough evidence
to 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 threshold
that was recommended. And then there are two recommendations on
neuroimaging. One, that a normal CT scan does not rule out
increased intracranial pressure. And I think that’s an important recommendation. And also, that routine repeat use of a CT
scan 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 level
twos 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, to
keep it less than 20. And that is interesting because the latest
adult 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 little
high. But we just don’t have the evidence to say
more. And the same as with cerebral perfusion pressure. We had a recommendation, once again, for a
minimum 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-specific
thresholds specifically for CPP, given the well recognized age-dependence of blood pressure
and 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 center
back in Cambridge, when you were there, was one of the best that came as close to giving
us a shot at doing that, and maybe future studies will be able to pin that down a little
better. So for hypertonic saline now, we do have a
level two recommendation for bolus administration of 3%, and with specific doses, and I think
that 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 comparison
between 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 also
was the only therapy that improved CPP, and that was kind of an exciting finding from
that. We also continue to have level three recommendations
for a hypertonic saline as a continuous infusion, and that was in the prior guidelines. But now, in other new 23.4% hypertonic saline
recommendation based on studies from down under, I guess you would say. Really exciting to see. You, I’m sure, and maybe the audience isn’t
as 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 armamentarium
with 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 studies
in regard to mannitol. It’s a really great point. And despite the history of mannitol use, I’m
really hopeful that ADAPT will now be able to– the ADAPT trial, led by Mike Bell, which
just closed 1,000 patients– it’s a comparative effectiveness trial funded by the NINDS, and
I’m really hopeful that is going to give us some insight into the effect of mannitol. Part of the reason we don’t have evidence
for mannitol is that some of the really early studies supporting its use were, in essence,
accepted. And people didn’t feel the need to replicate
them, 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’s
kind of a bummer, I guess you would say, but it doesn’t mean that we don’t recommend against
mannitol as an alternative to hypertonic saline. We just don’t have the evidence in the articles
to support its use. The other thing with regard to the hyperosmolar
therapy is that, once again, we have some safety recommendations showing that sustained
increases at high levels, and whether you pick 160 or 170, you start to see complications. And whether it’s evidence of an endotheliopathy
with 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 higher
levels. Also we had some other new recommendations
this time. Again, very exciting. A category that, I think, pediatrics has also
led the way in initially. We were kind of the first people to put a
chapter in on sedation. We didn’t have much to say, but it has– I
think it really stimulated some studies. This study out of Wash U showing that midazolam
and fentanyl combined, in particular, was associated with not an improvement in ICP
when 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 three
recommendation against routine bolusing of those agents. I think it’s really important, though, to
recognize 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 caregiver
to not sedate or provide appropriate analgesia to kids with severe TBI, but rather if you
are already doing that, just coming in with additional boluses don’t seem to produce important
improvements in ICP. Although, if you were to compare the study
from Wash U, Jose Pineda’s group, they saw, really, predominantly negative effects. In Steve Shein’s study, we saw some benefit
on ICP, but no benefit on CPP. I think taken together, it really argued more
for give boluses of hypertonic saline or other therapies if you are adequately sedating. And then, of course, another very important
difference 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 sedation
in 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 TBI
saying we can’t use it, you could argue there’s something at a higher level preventing the
use of it as a continuous sedation approach in pediatric TBI. I also wanted to mention that we don’t have
a specific recommendation on neuromuscular blockade, but we do say that its use is up
to the treating physician, and we deal with that a little bit more in the algorithm. We also have a number of other level three
treatment recommendations– cerebral spinal fluid drainage if you’re using a ventricular
catheter. Seizure prophylaxis, level three also, although
we didn’t have evidence to say levetiracetam, or fenotin, or fosphenytoin were better. Either was better. And then we also had a level three recommendation
against prophylactic hyperventilation. However, if you have refractory intracranial
hypertension, now kind of as a second tier hyperventilation can be used, and there is
a level three recommendation for it. And once again, I think that becomes a little
clearer on the algorithm. It’s kind of like what you use upfront versus
hey, we’re not winning, now what are the choices I have, I guess would be the way I would put
it. I think one of the greatest improvements in
not necessarily as much related to the new data as much as related to the interpretation
of it, has come with the temperature control, and we now have a level two recommendation. And now this, as you are talking, this is
with 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 immediately
cool them in kind of a neuro-protective fashion, and despite how wonderful that sounds, and
despite many animal studies suggesting that there was some potential for that, it’s just
never 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, there
were some trends in some of them for deleterious effects, and so we have a level two recommendation
against doing that. However, for ICP control, once again, if your
first line therapies are failing, moderate hypothermia to attenuate intracranial hypertension
is on the table. So it’s like a differentiation between what
you would do first tier, and then what you would do second tier. Exactly. A preventative strike with mild cooling is
not recommended. In fact, we recommend against it. Whereas if the conventional first line therapies
are failing, hey, this is something that is– there is evidence to say that it can control
ICP, and that’s a very different situation than upfront application. And similarly, for refractory intracranial
hypertension, we have level three recommendations, once again, for barbiturates, and for decompressing
craniotomy. And those are, basically, the same. There was a little bit more evidence supporting
them, but still, all at level three. I mean, perhaps, it’s also worth just mentioning
that we did have pediatric neurosurgeons review all of the evidence on the decompressing craniotomy
literature to go through that in really quite some detail as well. Oh, yes. That was something that, I think, in all three
guidelines, we have been very, very mindful to be inclusive on the team, and I think that
everyone felt comfortable with every recommendation. I think there really was a consensus on the
evidence portion. I think there was an excellent consensus even
on the algorithm, but there was strong agreement. And even recognizing that some centers use
decompressive craniotomy in a more prophylactic way. But I think the evidence that we can state
in 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 large
parenchymal 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 in
the guidelines. It’s a really excellent study, but it’s a
study on a very specific immune modulating diet, and the study was well conducted, and
thus, 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 difficult
to generalize beyond it. In contrast, we now have another new recommendation
to start nutrition within 72 hours. That approach has even stronger evidence subsequent
to the guidelines. Again, and that’s for improving overall outcome. It’s a level three recommendation, but it
did not differentiate whether you– exactly what kind of rate of enteral nutrition or
exactly what the recipe was, but I think it’s still a first step forward on that. And then finally, interestingly, the recommendation
on corticosteroid use moved from a level two against to a level three against. And people may not realize this, that we’re
humans putting together these guidelines. And the backdrop upon which they are crafted
changes with time. This, to me, is a really interesting example
that earlier on when the CRASH trial came out, it was a study of steroids in adults
with thousands of patients– negative, deleterious. It influenced the field like a hammer, and
I think that that study probably was given too much weight by us in the past. And as we’ve looked more rigorously and said
to 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 just
simply extrapolate. And the pediatric evidence is really level
three against corticosteroids. And the other thing I think that we are trying
to be very mindful of is that we don’t want to tie the hands of our caregivers to not
be able to use steroids in the setting of adrenal suppression. And whether it’s etomidate, or whether it’s
prior steroid use, or other problems– HPA axis. Sure, HPA axis injury. Absolutely. So I think in that setting, we moved that
from a level two to a level three. That’s one of the more interesting nuances,
I think. If you weren’t really looking carefully at
the 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 mentioned
that there have been other studies coming out since this was all written. And the question is do we have to wait another
five or six years before the next set of guidelines? Or is there going to be a completely different
strategy with dealing with new evidence as it comes out? It’s a great idea. Living guidelines is something that has been
discussed. I think that there is interest from the Brain
Trauma Foundation of doing that. It’s not easy, though. It takes a lot of work. And I think that it probably takes a certain
level 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 guideline
kind of is so logical now. Everyone just goes to their phone for what
happened last night. I think that is certainly where it’s going
to go. I think it’s interesting that we’re almost
in a scenario where the mechanics to make that happen in the transition need to be worked
out. And I hope it does happen, but I do think
that it’s not a trivial undertaking to do. That’s how I would describe it. I would think if we could update at least
every 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 document
or the algorithm. Perhaps, you could just sort of talk us through
the concept and the figures that appear there. Yeah, as I mentioned a little earlier, with
the first guidelines, there was an algorithm. At that point in time, we felt it was really
important. 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 driven
document. As I mentioned, the Brain Trauma Foundation
with a second edition really pushed for “We need pure evidence”, and kind of almost a religious
kind of approach. And this time around, I think it just became
so clear from the feedback that we received that people want more than that. And so we put together– and I’m really pleased
to say that the two of us together are the co-lead authors of this, and it’s a fantastic
thing. I think it’s one of the best things I’ve ever
been part of in my career. That tried to really build a much stronger
consensus layered upon the evidence, and address some issues that are really neglected, and
it 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, and
things 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 a
sterile 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 have
a 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 nicely
implement the therapy. But you’re stuck with the same sterile guideline. You know, things like weaning. You can read through all the guidelines, and
no 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 no
one ever discusses it. You just don’t find it in a document. And another point in the algorithm that I
think is really important– and this became– we discussed this– I think we were really excited when we started
discussing this in that thresholds that are generated in guidelines document are the minimum
threshold. 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 to
be in the 30s some time period. And we’re going, wow, but you’re stuck with
that. And so the algorithm article discusses, I
think, really nicely that these thresholds are minimum targets. And whether it’s a hemoglobin of seven, or
an ICP of 20, or a CPP of 40, or a brain tissue O2 of 10. Heck, you can find articles that say we should
use 25 or 30 as the target, but the strongest evidence, the most cautious, of course, is
10. And you might argue, well, why not just raise
those 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, pour
it 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 threshold
is one that we discuss in the algorithm. We would like, now, to turn to the audience
to ask a question. When you respond, please leave your city and
country. What did you find most helpful about the three
new 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 back
at 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, you
might have a patient that blows through this in a few hours, and then you might have another
patient that never progresses to second tier therapy. Some utilization of this allows you to do
all of your management. I think one of the other things about this
that I always personally felt we fell short in the prior guidelines is herniation is so
devastating. It’s just so important, and yet there are
no studies on it. Even in the adult side, there are only a few
studies on herniation. It’s really interesting if you look at those
adult studies. And you mean what would you would do in an
emergency? That’s right. And not only what you would do, but what are
the consequences? It’s not like well, we’re going to randomize
to A or B in herniation. That’s a little tricky. And not to say that it couldn’t be done to
try to improve what our best approach is on that, but I think one of the things– if you
look at some of the– I think there’s about three adult studies on herniation– the interesting
thing is that there is a pretty decent number of patients that herniation can be reversed. We think of it as it’s so devastating, and
rightfully so, but it’s not always. And the early signs and symptoms in some patients
can 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 herniation
pathway, and it has a nice backdrop on, well, what are the signs and symptoms because it
varies 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 mannitol
or hypertonic saline. It’s interesting, in the adult studies, it’s
usually 23.4% saline, but I think in pediatrics, people still– the guidelines committee felt
that in this setting, more people are comfortable with mannitol. And what we didn’t want to do was to try to
introduce something new in that crisis setting that people are trying to find something that
they’re not prepared for. Maybe that will ultimately evolve, but that
wasn’t the goal of this. And then, of course, if you have an EVD in
place, 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 on
there, if it saved one or two kids, it was a great addition to these. And then as I mentioned, within this, we have
a nice discussion about an ICP pathway, and how do you progress down it. And the CPP pathway– what do you do to add
to this? And then the brain tissue O2 pathway. And one of the things that’s always brought
up, well, how does one influence another? And the classic example I think that is really
a 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 get
to that. But now you have a patient whose brain tissue
O2 levels are low. Say, they’re seven or eight. And you’re saying, well, our ICP is under
control, but our brain tissue O2 is inadequate. Should we just be satisfied with that? A classic example is to say, well, let’s let
the pCO2 rise a little bit. Or let’s raise our blood pressure a little
bit. Hemoglobin. Transfuse. Yes, do an intervention that will maybe improve
brain 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 algorithm
papers 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 artificial
to really consider this a tier, et cetera? I think maybe in the past, we might have thought
to 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 really
more 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 much
more risky. And so if you’re not controlling ICP with
that first tier of therapies, you have choices. And as I mentioned, barbiturates, moderate
hypothermia, hyperventilation, and pushing osoms. I like the way this is presented, now, because
it’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 this
should 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’ve
had 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 individual
use or combination use, the efficacy depends on the center because I think that these kind
of advanced therapies, they take skill. They really do. You start barbiturates, you better be ready
to support hemodynamics. I remember Brad Peterson from San Diego saying
I 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 start
it and wait for trouble, you are all over it. You’ve got the presser, essentially, teed
up to the patient at the time you start it. And there may be some centers that are great
at decompression, and they want to go to decompression at that point. Obviously, the evidence, even on the adult
side, pretty equivocal on that also. So I do think this may vary, depending on
the center. And I think the other thing is that this whole
guidelines, the backdrop of it, is as if we are dealing with one disease. And we know now that it’s very likely that
the phenotypes of TBI are going to be important, and it may be that particularly for something
like 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 be
very different than someone who had a big subdural, and has a focal lesion, or a big
contusion. And so ultimately, this will evolve to something
much more elegant. We would like to turn again to our audience
to ask a question. When you respond, please leave your city and
country location. What do you think might be changed to improve
the value of future guidelines to caregivers? And the other component of this, if we’re
going to go to these advanced therapies in the second tier, we’ve also got a section
on advanced neuro-monitoring. And there wasn’t a great deal of evidence
in 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 use
neuromuscular blockade, we strongly suggest using continuous EEG. And obviously, once you start to get into
these 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’s
nice to have advanced monitoring as much as you can from the word go. Recognizing that you don’t overreact to any
one monitor. I really think that as with therapies, I’m
a 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 trouble
is almost being a zealot about one approach, and pushing it, really, and I think that we
see in all of these therapies that the toxicities are dose-dependent. And so if you can use a little of a lot of
therapies, almost like an artist, you can– and with many advanced monitors, I think that
that’s one of the ways that you can optimize outcome. I don’t think we’re there yet in a guideline
or 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 want
to pull you back on, and sort of garner your thoughts on, that’s the question of what if
we haven’t got invasive ICP monitoring? What do we do? I think that is, really, a burning hot question
right now. That was really set into motion by Randy Chestnut’s
best trip study published in the New England Journal a few years back. And then more recently, Tellen Bennett’s JAMA
Pediatrics paper, and questioning whether this is, really, the key target that we should
be aiming for. And I think it’s so interesting because we’re
really excited that we actually do have a section in the algorithm article about this
question. And the real gap, though, is that if you don’t
use ICP monitoring, that there is no pediatric, not only data, there isn’t even a consensus
or single center description of how you should manage it. And in Tellen’s paper, which wasn’t a study
of how to do it, it was just the way some people are managing what’s happening– what
are the consequences? Can we use statistics to try to sort this
out? And in that paper that questioned it, there
was no protocol. There were some percentages of what percentage
of people use barbiturates, and what percentage of people– so A, we don’t really even have
a document in pediatrics. But we do have Randy Chestnut in the supplement
to 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 of
that paper, there’s some truly fascinating results. One is that in many cases, the amount of therapy
that was used was greater than if you used ICP monitoring. It kind of makes sense that if you just have
to guess at what kind of brain swelling there is, that you’re going to need to overshoot
because if you run it too thin, then you could get into trouble. And so, obviously, using those metrics– exactly
how 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 have
to 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 than
the evidence based on ICP. So you can’t get around the ICP influence
on 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 the
phenotyping. That we have underutilized imaging to help
us guide our treatment. Not so much we don’t get enough imaging, but
we, in general, have gotten imaging to say oh, they need to go to surgery, rather than
wow, 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 longer
period 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 other
than 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, to
be published. And remarkably, it seems like the number of
centers that don’t use ICP monitoring– or use them in selected patients– is pretty
substantial. The other thing that I would say about that
is 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 adapt
gives us some clues as to how to better manage. I’m hoping that based on adapt and the other
studies, that we actually become better at utilizing and treating ICP, and that it will
lead to better outcomes, rather than trying to take a step back and fly blind, I guess
would 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 of

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