Guidelines Review: Management of Severe Traumatic Brain Injury

Podcast Transcript

Introduction: Neuro Pathways, a Cleveland Clinic podcast exploring the latest research discoveries and clinical advances in the fields of neurology, neurosurgery, neuro rehab, and psychiatry.

Glen Stevens, DO, PhD:

Head injury is a particularly difficult topic to study and good evidence is scarce, coupled with the fact that trauma arises in an emergency, making traditional clinical research design more difficult. Those on the front lines of managing patients with severe traumatic brain injury are at a disadvantage in having both evidence-based and real world relevant guidelines to direct care.

In this episode of Neuro Pathways, we're discussing the evidence and guidelines that are available, and how this work is evolving to better support healthcare professionals in the field. I'm your host, Glen Stevens, neurologist/neuro-oncologist, in Cleveland Clinic's Neurological Institute. I'm very pleased to be joined by Dr. Greg Hawryluk. Dr. Hawryluk is a neurosurgeon serving the level one trauma center at Cleveland Clinic Akron General, and medical director and chair of the Scientific Advisory Board of the Brain Trauma Foundation. There he is at the forefront of writing neurotrauma treatment guidelines that are followed by trauma centers around the world. Greg, welcome to Neuro Pathways.

Gregory Hawryluk, MD, PhD:

Thanks for having me, Glen.

Glen Stevens, DO, PhD:

Greg, it's always great to have a fellow Canadian on, and I always have to mention that if we have a Canadian on, because I think personally it's important. But otherwise, tell us a bit about yourself and what brought you to the Cleveland Clinic, and specifically to Akron.

Gregory Hawryluk, MD, PhD:

Yeah, most certainly. So I'm a neurosurgeon. I did my training in Toronto and that was both a basic science PhD and my neurosurgery residency. And I've always sort of been the oddball neurosurgeon. Most neurosurgeons, they elected to clip aneurysms, and I was always sort of the oddball that was really interested in the trauma. And I think to a lot of neurosurgeons, trauma sort of seems like it's simple, it's easy.

But I think the reality is that when you really get into it, it's none of those things. A lot of people run away from an emergency in a crisis, and I've always been the kind of guy that runs towards one. I've always been a bit of an adrenaline junkie and someone that performs better in a crisis than I normally would. So I think it's been my personality that's drawn us to it.

And I think the other thing is that this has always, to me, been really meaningful medicine. Head injury just has such a profound impact on patients. Brain damage, it always sounds scary and frankly, I think it is. A head injury can profoundly change a person, their ability to work, do the things they normally do. And it's something that I've wanted to help with. And I think it's commonly said that things with the brain, in particular, head injury cure has been slower to advance than other areas of medicine. But I'm excited. I think over the last 10 years we're finally starting to see some progress on some things. And I've really enjoyed my role with the Brain Trauma Foundation in developing some of these guidelines, because the single biggest thing that's ever helped head injury actually has been the guidelines.

Glen Stevens, DO, PhD:

So let's move in that direction. Let's start the conversation historically. So maybe go back in time before the guidelines were initiated. What was the state of CNS trauma prior to the guidelines?

Gregory Hawryluk, MD, PhD:

What I would say is that the really key date with head injury is 1974. So prior to that, it was the dark ages. But a couple things happened in the seventies. So the first thing that we got was CT scanning. So for the first time, we started to be able to actually image the brain, see where there was blood, and really did get a better sense very quickly of if someone needed surgery and what that surgery should be. The other thing that maybe was even more important was the Glasgow Coma Scale.

How many things in medicine have survived 40 years, or anything in the world for 40 years? And I think what's been fascinating about the Glasgow Coma Scale is that it has stood the test of time. And it's sort of interesting because prior to 1974 and the publication of the Glasgow Coma Score, it was really hard for us to even talk about a head injury.

We didn't have a common language for when is someone getting better, when is someone getting worse, when should we do surgery? Really, any literature before the GCS is a bit meaningless. So those two things really opened the doors to finally allowing us to make advancements with head injury care. And things picked up actually fairly quickly after that. So in the 1980s, there was a huge amount of work that went into both head and spinal cord injury, both forms of CNS trauma. And one of the very first things that we started to recognize was the issue of secondary injury. And so this is the idea that for weeks and maybe even months after an injury, there's actually ongoing injury that happens. There's a bunch of pathological processes at the cellular level, the molecular level that occur. And so that started to give us the idea, well, maybe we can target those things with drugs.

But the other thing that started to happen was there was this rise in evidence-based medicine. So we've seen that all across medicine. And maybe the reason that we saw it early on in head injury, and I think it's because we had a late start with the academics -- wasn't until 1974 we actually did reasonable research. We actually have a small pool of evidence helping to inform head injury care. And maybe that's why things started with head injury. So the BTF guidelines were the first ever guidelines ever published by a surgical specialty. And maybe it's because it was easy, we just had a few studies to put together. What's been really exciting about those guidelines, so they were first published in 1996. Here's another Canadian connection. So the idea for this: there were actually three neurosurgeons that met in a bar in Vancouver, Canada.

So they were up there for a big neurosurgery conference, and they had this idea. Someone had just published methodology for doing guidelines. They had actually just done a study looking to see, are centers doing consistent things? Are they following the evidence? And they found that the centers weren't. So they sat down and they said, it was Jam Ghajar, Randy Chesnut and Don Marion were the three neurosurgeons that met in Vancouver. And they sat down and said, "You know what? No one's ever done this before in surgery. Why don't we do a guidelines?"

So that effort was fairly quickly published in 1996. What's amazing is that if you look at the guidelines today, we've got guidelines with the Brain Trauma Foundation on all sorts of head injury subtopics. We've published over 15, I think we're at 18 now, full guideline efforts. We do pediatrics, we do combat, we do pre-hospital guidelines, even concussion now.

We actually haven't changed the format of those guidelines too substantially since 1996. And they've had quite a legacy. I think we would all think that if a scientist in his lab came up with a pill that helped outcome from head injury 5%, if we could get a 5% mortality reduction, that would be Nobel Prize stuff. That would be exceptional. What's amazing is that these guidelines, they have actually led to a 50% reduction mortality just by following these guidelines. So it's had a dramatic benefit to patient care, and it's been the honor of my life to really take the reins of all these different guidelines and to try and modernize them and try and improve upon these benefits that we've already seen.

Glen Stevens, DO, PhD:

So I'm just going to tell a little anecdote here since I was very well aware of the seventies in university, in the seventies and the CT scan. And I always like to ask the residents, what's the association between the CT scanner and the Beatles? And the answer is that Hounds Field, who is instrumental in the development of the CT scan, of course the Hounds Field units, and he won the Nobel Prize Hounds. Fields's research was covered by the same group that managed and got the royalties from the Beatles records. So indirectly the Beatles funded Hounds Fields's research that allowed us us to have the CT scan and hence we move forward. So just a little interesting anecdote. So prior to your guidelines in 1996, if I have a head injury and I come into the hospital, how's the treatment changed? Were we giving steroids then? Were we hyperventilating? What sort of verboten now that was being done then?

Gregory Hawryluk, MD, PhD:

That is a really great question. And the funny thing about these guidelines is that these guidelines say far more about what you shouldn't do than what you should do, which I think is sort of funny. But that that's really how the evidence panned out. And it turns out that, prior to the guidelines, people were doing all sorts of stuff that we wouldn't do today. So a really good example is dehydration. So back in the eighties there was this view that we all know that after a head injury, brain swelling is one of the biggest problems that we have to face. And the idea was, well, let's really try not to give these patients fluids, let's dry them out and hopefully that'll reduce the brain swelling that they have. And that has been very clearly been shown to be the incorrect approach. So we now know that that fully resuscitating these patients is very important and leads to better outcomes.

In fact, it was Randy Chesnut that showed that if a head injury patient has so much as a single blood pressure that's too low it's associated with a double rate of mortality. So that was one of the things we were doing wrong. Another thing was, as you mentioned steroids, the idea has always been, well, we know with brain tumors that we can give steroids and it reduces the brain swelling. The big problem is that there's a couple of different kinds of brain edema. So there's vasogenic edema where the edema is in between the cells. There's also cytotoxic edema where the cell itself is swelling. And for the second type, the cytotoxic edema that we really think is the big problem after head injury, steroid don't work for that. And in fact, we have no probable benefit and all the risks of the immunosuppression. So it's one of the few things in, well, in fact, it's the only thing in head injury that we have level one evidence for.

So we had the large crash mega trial, so they enrolled over 10,000 patients and showed beyond a shadow of a doubt that if you give a head injury patient steroids, they have worse outcomes. So that is one of the, now perhaps the biggest flagpole in head injury care is not to give steroids. The other thing that was very common in the eighties was hyperventilation. So let me be clear that there's still a role for hyperventilation. It's still something we use in an emergency, but common practice in the eighties was to hyperventilate patients drastically and for long periods of time. And what we now know is that that was harmful because that actually reduced blood flow to the brain to a point that was harmful. And that's yet another thing that the guidelines now say not to do. So there's certainly some things that we're learning about that we should do, but ironically, the biggest thing the guidelines achieved was stopping some of these harmful practices.

Glen Stevens, DO, PhD:

So let's go there then, instead of the things that we shouldn't be doing, what have the guidelines showed us that we should be doing?

Gregory Hawryluk, MD, PhD:

So I think that the biggest thing that is helping head injury is supportive care. So what we've learned is that there's critical values of brain pressure, of blood pressure, of brain oxygenation, and if we can hit certain threshold values, that's associated with better outcomes. So for the last 20 years we've been refining what those numbers are. For instance, brain pressure, the critical value used to be 25 millimeters of mercury. Further research led to, in the second edition, we said, okay, 20 millimeters mercury now. Today the value that we use is 22 millimeters of mercury. I'm actually really looking forward to when we work on the fifth edition. So we're currently in the fourth edition of the adult severe head injury guidelines. We should be starting work on the fifth edition in about three years. And what's really interesting is that we've had a couple of recent papers that suggest that values as low as 10 might actually have some harm associated.

So in the future we may revisit what those critical numbers are, but there's other places that the guidelines I think are bringing forward new treatments. One of them has actually been antibiotic impregnated, external ventricular drains. So for those that aren't neurosurgeons, one of the very common things that we do in a head injury is we'll actually put a tube through the skull down into the fluid filled chambers of the brain. And that does a couple things for us that allows us to measure the pressure in the brain, to make sure we're below that 22 number, but it also allows us to drain brain fluid to help achieve that.

And in a patient in a crisis, even one CC can be critical. And I remember as a resident physician, one of the major complications of these tubes was that they could get infected. And then if someone got ventriculitis, they would spend sometimes months in the ICU going through cycles of trying to clear the infection and then trying to put a, for instance, a shunt in. And now that we have antibiotic impregnated drains, that really has been a game changer. So the infection rate, leaving those in as long as three weeks, is very rare now. So we now have evidence, for instance, to use these. Another thing that we have evidence for now is feeding patients. So if you re-initiate feeding within the first week, those patients do better. So there's an awful lot of stuff in the guidelines that I think is helping us to provide better care to patients.

Glen Stevens, DO, PhD:

So for those out there listening that may be seeing people that don't have severe traumatic brain injury, that what we're … do the guidelines also discuss concussion, those types things? Or is it really mostly just for those that have severe trauma?

Gregory Hawryluk, MD, PhD:

Yeah, so what I was saying is that the Brain Trauma Foundation really made its mark, at least initially on severe head injury. We actually have published a couple of guidelines on concussion, and I think we've had a lot of hope for those guidelines that the problem with the concussion field is there's over two different definitions of concussion. People use terms mild traumatic brain injury, concussion. Are they the same thing, are they not? And so the real problem in concussion has been a lack of uniformity in definitions. And we had really hoped that if the Brain Trial Foundation stepped in, that the Brain Trial Foundation has really been a unifier. They brought a lot of different thinkers together. They've got people talking the same language. And I think one of the things with guidelines is they create a framework for how you think about problems. And so the BTF has stepped into the concussion field.

They've looked at how should we be defining a concussion? And I think we've sort of come to the notion that probably we need to define concussion based on symptomatology. The other thing that BTF has tried to do with concussion is to look at concussion subtypes. Some people have ocular motor problems where they have double vision, other people have problems with cognition, some people with sleep. And the idea is: one-size-fits-all probably doesn't work that well for concussion.

Maybe we need to recognize that there are different patients with different symptoms. Those different symptoms need to be treated differently, and that perhaps if we really tailor treatment to these patients, their outcomes may be better. So we're compliant to continue that. The BTF has just started into a big collaboration with the Department of Defense in the US, and the big question we've been asked to inform is the issue of readiness. So if you've had a concussion, when are you ready to go back to sports? When are you ready to go back to combat? So that's the next problem we're going to be tackling with concussion at the BTF.

Glen Stevens, DO, PhD:

I was going to ask this later, but I'll just jump in now since you brought it up. But obviously a lot of war's going on these days, so probably see a lot of head injury with the Department of Defense. So I was going to ask you what your interaction is with the DOD for the foundation?

Gregory Hawryluk, MD, PhD:

So what happened is, I actually have an academic appointment with Uniform Services University, and it really stems from the fact that the military sees head injuries that the civilian world just doesn't, and they have unique expertise that the civilian world needs to learn from. So we've really grown together. The first project that I've done with the military, we're actually halfway through right now doing a penetrating head injury guideline. And we recognize that here in the military, they're the leaders.

In the civilian world, very few centers see any reasonable volume of penetrating head injury and really get enough experience to start generating wisdom. I think that the really good example of this is if you go back to Vietnam, it was the military that started the practice of minimal debridement. Before that, there had been a thought, if there's a bullet fragment in the brain, we're going to root through all that brain and try and get every last little bullet fragment out to try and prevent infection.

And what they found is that that is very damaging to the brain and to the function of the patient, and it doesn't necessarily prevent that infection. So the military changed the practice and they said, okay, we're just going to take out the shrapnel that's easy to get. And that experience led to a change in civilian practice. So with this new penetrating hemorrhaging guideline that we're doing with the DOD, the military that said,"We want to work with the BTF on this because we think it's time to change practice again".

So they've got this new practice paradigm where they're very aggressive initially. They're trying to do damage control surgery early on, they're trying to prevent CSF leaks early and they feel that they're getting better outcomes. And what's really remarkable is when you consider a military gunshot wound to the head, we're talking about really high caliber weaponry and their outcomes in the military now are better than in the civilian realm, which with handguns, which are sort of puny compared to what they face in the military. So there's no question the military's got something figured out, and we're just trying to tap into that wisdom and bring it into the civilian world and make some guidelines.

Glen Stevens, DO, PhD:

You discussed CSF a little bit earlier, but you've had some involvement with the DOD looking at intracranial hypertension in the CSF drainage, right?

Gregory Hawryluk, MD, PhD:

Yeah. So this is a really interesting idea. So Jam Ghajar has long raised the question: if you could go in early after a brain injury and drain out some of the cerebral spinal fluid that's in there, is it possible that you could prevent a lot of those problems that we see in the ICU where patients have very high brain pressures for a long time? And let me be very clear that this is a very controversial idea, and I think every listener should be aware that at the moment doing a lumbar puncture on a patient with a head injury, be very careful because we do think there's a risk of precipitating herniation. If you go right back to the origins of lumbar puncture over a hundred years ago, in some of those early cases, there were descriptions of herniation. So we want to be very clear that this needs to be done carefully, but there's actually many groups around the world that have had an interest in exploring this practice.

There's a group that's published what they feel are safety criteria based on CT imaging features. So Dr. Ghajar has really brought the Brain Trauma Foundation to doing its first real ever research project looking at this idea. Usually the BTF synthesizes other people's work, but we're actually trying to contribute to knowledge now by doing this trial. So the idea is going to be in very carefully selected patients, to try draining some CSF with a lumbar drain, and see if we can avoid getting into problems with brain swelling down the road.

So the DOD is interested in the trial. We've had a tentative green light to do this study. Head injury is a field where we have been struggling to advance. Again, we're still waiting on that pill that makes a head injury better. I would say that, as someone that's looked really critically at some of the tenets of head injury, I think that we've got some things wrong and it's a field where we need to challenge dogma. So I think it's a very interesting idea to challenge this dogma. And maybe there is a role for draining lumbar CSF in some of these patients. And I'll say that the military is actually interested in this because that this may be something that they can do in a combat environment where they don't have a neurosurgeon. So let's see where that research goes.

Glen Stevens, DO, PhD:

Well that was helpful because I was curious as to whether or not the foundation is involved in upfront trials where it's mostly a retrospective review of what's being done. And it sounds like it's previously been more retrospective and now you're starting to do some forward trials.

Gregory Hawryluk, MD, PhD:

That's absolutely the case. The frustrating thing with doing the guidelines, and it's led to a lot of introspection at the Brain Trial Foundation, because at the end of every guidelines chapter we've ever done, we write down, "Well here's the evidence we wish we had. Here's the critical questions that someone needs to do a project on". And it's really frustrating when you go from the second to the third to the fourth edition, and those holes aren't getting filled. So I do think that going forward, one of the things the BTF wants to do is to start contributing to some of those answers, not just adjudicating other people's research.

Glen Stevens, DO, PhD:

So that sort of moves us along as we get closer to the end. And that is what is the next phase? What are some of those questions? What are the things that wake you up at two o'clock in the morning and you have to write your idea down?

Gregory Hawryluk, MD, PhD:

I am one that really thinks that we have got some things wrong in terms of just the basic foundations of head injuries. So one of the things that is a real passion of mine is how I actually think the Kelly Monroe doctrine is incorrect. So medical students out there, don't go writing this down on your exams because what I'm about to say is not, I wouldn't call it accepted. But hear me out on this. So one of the things that I was surprised to learn about a head injury is: one of the very first people that really studied intracranial pressure was Nils Lundberg. And one of the early experiments that Nils Lundberg did back in the sixties, the key paper. What they decided to do was they decided to radio label albumin, and they just looked at the Geiger counter spikes over time in patients sitting in the ICU.

And what was really fascinating is this happened in a time, first off, they put a lot of ICP monitors into medical students, which we obviously don't do anymore. But it was also a time where people didn't really understand that increased intracranial pressure was harmful. So the experiments that were done, we couldn't repeat today. And what they found is that when we see these plateau waves where the ICP goes up high, stays high for a while, their initial observations argued against the Kelly Monroe doctrine because, to my surprise, when the plateau waves of ICP were seen, the Geiger counters went nuts. And what this meant is that actually the brain blood volume was increasing, not decreasing. We were always taught with the Kelly Monte Monroe doctrine, the brain is a fixed box. The volume of one thing goes up, you have to squish out blood, but that's actually not what happens.

What I think a lot of us now know is that what drives the brain more than anything, perhaps, is autoregulation. So when the brain isn't getting enough of something that it needs, whether it's oxygen, glucose, a very long list of metabolites, what the brain does is it will dilate its blood vessels to try and get enough of that thing it's not getting. And so that dilatation of the arterials increases the brain blood volume and ultimately the ICP. So one of the things that I was involved with a few years back is the CEEBIC algorithms. So what I did is I brought together 42 of the world experts in head injury management, and we tried to fill in the gaps so that the guidelines traditionally have only dealt with published evidence. And the problem is that sometimes there's a gap between that evidence and what to do at the bedside.

So the only way to fill that gap is with expert consensus. And one of the biggest things to come out of that effort was the notion that we as clinicians caring for head injury have to start understanding some of these autoregulatory principles. We have to be able to test autoregulation and we have to be able to adjust treatment a accordingly. So for instance, if we know that autoregulation is intact, one of the strategies that we can use is we can actually push up the blood pressure that gives the brain more of what it needs, and the brain will respond with vasoconstriction, and that reduces the cerebral blood volume and the intracranial pressure. So I think we're still unlocking all sorts of mysteries about brain physiology, and I think we're learning more and more that that's the horizon, is to learn more about this brain physiology and to exploit it at the bedside.

I think in terms of practical issues, that's one of the things we're doing at the Brain Trauma Foundation now we're now looking at our evidence-based recommendations as being sort of the penultimate step. So that's not the end of the story the way it used to be. Now the final step in making a guideline is to bridge that evidence with a consensus process. So the BTF didn't used to want to get into consensus because they said, "Well, we do evidence. We synthesize evidence. Consensus is something separate. Make that a different project". But what we really found when we published the most recent fourth edition is people were unhappy because they said, we get these legalese documents that tell us what the evidence is, but they don't tell us what to do at the bedside. So I think to better serve the physicians that need our help, we're trying to bridge that gap with expert opinion.

Glen Stevens, DO, PhD:

Excellent. So I'll ask you one more question before we close it down, and can you talk just briefly about autoimmunity following brain injury?

Gregory Hawryluk, MD, PhD:

That is a question that really interests me. So I often joke that I'm trying to star in the sequel to concussion. So I've got this crazy idea that we learned back in the 1990s. So if you remove someone's brain decades after they've had a brain injury, they still have way too much inflammation in their brain. And the question is, why is that? So is there something self-perpetuating about a head injury, or maybe is something else going on? And what I would say is that neurologists tend to get this. I mean, you're a neurologist, and for me to tell you things about autoimmuninity to the brain, neurologists know that. But I don't think neurosurgeons have been thinking about this. And we have to remember that the central nervous system is supposedly immuno-privileged. So normally the body would view the brain and spinal cord as being foreign.

And so what we know is that after a head injury, we have a couple things happen. We spill brain and spinal cord antigens into the bloodstream after an injury. The other thing is that the blood brain or blood brain barrier's disrupted, so immune cells start to get in and see CNS antigens that they didn't used to. So my crazy idea has been that perhaps chronic traumatic encephalopathy is actually the sequela of a grumbling autoimmune process. And so I did an experiment. I'm also a basic scientist, and what we did is we looked at spinal cord tissue injected under the skin of rats. So we never touched the central nervous system of those rats. We simply inoculated the rats with spinal cord tissue. And that was enough to cause encephalitis. And in fact, we know that the prevailing model of multiple sclerosis has been basically that model.

So the experimental autoimmune encephalomyelitis model has long involved that sort of sensitization. It usually uses an adjuvant, which we don't provide in a head injury, but it's caused me to ask a question that might sound a bit crazy. The question I'm interested in is: should we be immuno-suppressing patients after head injury?

The person that sort of paved the pathway for that line of thinking was actually a mentor of mine, Ross Bullock. And he was looking at cyclosporine for head injury. He published a paper, demonstrated it was safe. The benefit of cyclosporine was actually thought to be mitochondrial stabilization. So one of the many things that happens with these secondary injuries after an initial injury in head injury, mitochondria get holes in them, something called the mitochondrial transition mega pore, and cyclosporine actually inhibits that from happening. So I think that there may be an additional benefit to immunosuppression that may be preventing this autoimmunity that may just grumble on for decades and eventually lead to something like, like CTE.

So I'm interested in asking questions around some of the new targeted treatments for autoimmunity, things that are cleaner than cyclosporine. And the question would be: i,s a short window of treatment for a week or two after an injury enough, or potentially, do some people need this treatment for the rest of their life? So once again, to the medical students out there, this is maybe crazy thoughts, but in a field that is failing to advance in many ways, I think it's a field that does need to challenge dogma, and I think we need some new ideas. And those are some that I'm pursuing.

Glen Stevens, DO, PhD:

So it sounds like the answer is go to the Brain Trauma Foundation, read the guidelines.

Gregory Hawryluk, MD, PhD:

There's a lot of good stuff in there.

Glen Stevens, DO, PhD:

A lot of good stuff there.

Gregory Hawryluk, MD, PhD:

Absolutely.

Glen Stevens, DO, PhD:

Well, thank you, Greg for sharing your insights today. I found it fascinating, not just because you're Canadian, but the content. Really excited to see how the field continues to evolve, and we're happy to have you at the Cleveland Clinic. Thanks a lot.

Gregory Hawryluk, MD, PhD:

Thanks for having me.

Conclusion: This concludes this episode of Neuro Pathways. You can find additional podcast episodes on our website, clevelandclinic.org/neuropodcast, or subscribe to the podcast on iTunes, Google Play, Spotify, or wherever you get your podcasts. And don't forget, you can access real-time updates from experts in Cleveland Clinic's Neurological Institute on our Consult QD website. That's consultqd.clevelandclinic.org/neuro, or follow us on Twitter @CleClinicMD, all one word. And thank you for listening.