Apr 1, 2016


Announcer: A conversation with the Neurotrauma Masters, that's next on The Scope. These are the conversations happening inside health care that are going to transform health care. The Health Care Insider is on The Scope.

This episode of the Health Care Insider is a little bit different than our previous episodes. Normally, we try to keep our episodes about 5 to 10 minutes long. This one comes in at about half an hour, but there's a good reason for it.

Recently four of the biggest names in neurotrauma came to University of Utah Health Care, and they talked about a wide array of topics, including some of the biggest challenges facing neurotrauma and what the future might hold.

They talked with their host, Dr. Greg Hawryluk, who is the Director of Neurosurgical Critical Care at University of Utah Health Care, for over an hour. We have condensed that conversation in to this half hour conversation you're going to hear right now on the Health Care Insider.

The first voice you'll hear is your host, Dr. Greg Hawryluk.

Dr. Hawryluk: We are calling our event A Day With The Neurotrauma Masters, and I think, as many people know, we really at the University of Utah have had the ambition of starting up a neurotrauma program. We thought a lot about what we best to do that. But what I thought would really take us to the next level is if we brought the most important people in the history of neurotrauma all here at the same time for a very special day.

So amongst the distinguished guests that we have here, we have three different continents represented. We have three different generations of neurosurgeons, and I am just thrilled that they are here to pass along their advice, their words of wisdom, the lessons that they have learned over the years.

So Andres Rubiano is currently in Bogota, Colombia. Andres has not been in practice actually all that long, but he has transformed Colombia. It's remarkable what he has achieved in a short time in terms of improving Colombia's neurotrauma and frankly their trauma care services.

Dr. Ross Bullock, I would probably describe as being perhaps the respected senior statesman in the head injury field.

Next is Dr. Michael Fehlings. I think there would be no debate he is, I think, the undisputed champion of all things spine and certainly spinal cord injury.

A very, very special guest, Sir Graham Teasdale. It's pretty hard to introduce such an important person. We can just say he invented the Glasgow Coma Scale. He has changed the world. He's come out of retirement to be here with us, and we are absolutely thrilled to have him and all these Neurotrauma Masters.

I am stunned that we have been able to get all these people together, and the lessons we've already started learning from them have been so wonderful and important.

So maybe the first place to start is, despite some very important areas of progress in neurotrauma, I think it would be fair to say that neurotrauma is lagging a bit behind other areas medicine, in particular things like oncology. I'm just curious for the insights of the panelist to their thoughts on that comment and why they might agree or disagree with that.

Sir Teasdale: Can I start as an old master of . . .

Dr. Hawryluk: The Grand Master.

Sir Teasdale: Well, I think because oncology is so much easier. You know, it's a much more simple problem. You've got a few genes working wrongly, and the thing progresses in front of you. You have the ideal opportunity to intervene as a disease is developing and abort it, do what you can to it.

Neurotrauma is the reverse of that, and this is the crux of the problem. In most severally injured people, whether it's brain or spine, most of the stuff is over before they get to you, and you're working against the clock. So I think that the effort has been great, but they are fundamentally different problems and it takes much better, more cleaver people to do neurotrauma.

Dr. Hawryluk: The Glasgow Coma Scale was a significant advance in helping us try to summarize the way a patient would present. The challenge, though, is that patients are very heterogeneous, and no two patients with a traumatic brain injury are the same. No two patients with a spinal cord injury are the same. This poses challenges in terms of management. It poses challenges in terms of research trials. I think trying to get a handle on that heterogeneity is going to be very critical.

The second issue is that, despite the advances that have occurred in the pathobiology of understanding the primary injury, the secondary injury, we really lack effective treatments that can target this, and I think this represents a significant challenge for us to address.

One of the challenges is that the vast amount of the damage occurs at the time the injury. We're fighting the clock. We're fighting the secondary injury cascades. We're trying to get 10% to 20% improvement, and so trying to see those effects is challenging.

A third area relates to the fact that, despite the popularity in the lay press of the concept of plasticity of the injured brain, the sad reality is that the adult brain and spinal cord actually show relatively limited plasticity in severe injuries, and so our ability to influence repair and regeneration is very limited. We see the promise of regenerative medicine, and I believe that we actually are right at the beginning of a remarkable era of where the discoveries of regenerative medicine might be applied to the challenges of neurotrauma.

Dr. Bullock: People have compared the complexity of neurotrauma to the complexity of the cosmos. If you think of the brain as having the similar number, at least orders of magnitude of functioning units, neurons, to the number of stars that are in the heavens, and the interconnectivity and inter-functional complexities have only just begun to be understood.

People say that 50% of what we learn to be true today will be wrong tomorrow. So these are all the kinds of levels of complexity, and as Graham mentioned, it's all over in an instant and a few milliseconds sometimes in the case of trauma.

But in terms of what we can and cannot do things about, one of the biggest problems is being that even though we've got something like 80,000 publications now published, since the Second World War, in the field of neurotrauma, we only have about 24 major clinical trials completed, and most of those trials have been regarded as failures, negative trials.

If you look at field like AIDS research, the numbers of papers of course are far more. There have been 600 major Phase Three trials in the AIDS research to get us to these therapies, the heart and other therapies that we have available now in AIDS.

So it's much, much harder to do clinical trials in neurotrauma, specifically brain injury, because you have to enroll the patients as early as possible, within hours of the event. Whereas in cancer therapy, you can enroll them within days, months, weeks of onset of the disease. So it's very difficult to be able to do that.

The government has made big advances by allowing ethics bodies, IRBs to use waived consent, and this is an important way forward to do more clinical trials. Clinical funding bodies and the drug companies have been very reluctant to fund TBI trials because of these negative trials that we've had in the past.

So these are all obstacles and hurdles that we need to get over. But there's one other thing, and that is teaching and the continuum of training. Only 8% of U.S. neurosurgical trainees express interest in progressing further in neurotrauma. So these guys are a rarity, and we need to encourage them.

Dr. Rubiano: I want to make a little bit emphasis on what Dr. Bullock was mentioning about the awareness and also the requirements to promote more in young generations the advance in neurotrauma care. If you go to many, for example, neurosurgical meetings in some regions, in the general program they never have or there is a lack of sections related to neurotrauma. That's why so many other areas, like oncology and vascular and other things have been promoted more.

I think other than all these advances that have been doing in the specific care, there is something that is recently opened and is the execution about the context of care. That is also related to improvement.

I think Dr. Fehlings has been doing research in timing for spinal cord injury and also when to take the decision in an appropriate way, and it's the same in many other areas.

The related issues with human beings and interactions with all these new technologies and all these guidelines, for example, is really important at the end, to see how these can influence the outcome of the neurotrauma patients. I think with progress we can show that it is possible to change outcome, that we can show to governments that it's important to invest and it's important to promote more advanced training in neurotrauma care. We can show to the government that if you can invest a little bit more in training and technology for care, you can save a lot of money from the system.

Dr. Hawryluk: All right. I have got one for Dr. Bullock. Dr. Bullock has had a very important role in head injury guidelines over the years, and one of the main thrusts of the head injury guidelines has been ICP monitoring. In fact, in a lot of studies, it's been said that if you're monitoring ICP, then that's convincing enough that you're actually following the guidelines.

As we all know, there's been a recent randomized control trial looking at the benefit of ICP monitoring, and it really was not supportive, and in fact we've seen a lot of companies reporting a decline in sales of ICP monitors. So I'm very curious for Dr. Bullock's respected opinion on that study and the current utility of ICP monitoring.

Dr. Bullock: Thank you that Greg. I think the first important point to make is that no form of monitoring is any use at all unless you act on the data that you get from the monitoring. We all know that all of us who in this room take care of head injured or any other type of patient, you can look at the number. If you don't do anything about the number, it means nothing.

Think about the pilot, when a pilot is flying a plane, it doesn't matter what the altimeter is showing, it's what the pilot does with the information that counts.

So I think that this trial that was done in some of the poorest hospitals in Bolivia in South America. Now, you know, that trial could have been performed in many other places, but it was performed in an area where there was no tradition of the use of intracranial pressure monitoring. In other words, the ecology of the environment in which the trial was done was completely wrong. There was no expectation or knowledge how to manage high intracranial pressure based on monitors in those ICUs.

So it's almost like the cargo cults at the end of the Second World War. If you put a jeep in front of a Pacific Islander with no roads and who doesn't know how to drive, the jeep is useless. So you really have to have the context correct.

Then to go on and generalize that this trial should inform the rest of the world about monitoring head injury differently is completely wrong. I think the one fact that was buried in the report of that trial is that among the patients who had their pressure monitored in that trial, the average time with high intracranial pressure, above 20, was 20 hours to 24 hours. That was the mean time of high intracranial pressure. Who of us would accept that? I mean that just shows that they didn't act on the data that they were given.

So I think that, first off, kudos to the group Dr. Chesnut and his group for being able to do a trial in one of the most impoverish environments in South America. That's wonderful, and they had about 98% follow-up of those patients. The trial revealed a huge amount of really useful data, but one of the things it did not tell us is that ICP monitoring really doesn't have a role to play in the future. It's how we do or what we do with the data that really makes a difference.

Dr. Hawryluk: Very good. So next I have a question for Dr. Fehlings. Dr. Fehlings has made many, many important contributions to the spinal cord injury field. But I would say that his opinions, with respect to steroids for spinal cord injuries, have really been particularly important for the field. It's hard to talk briefly about steroids for spinal cord injury, but I'd be very grateful for any high level thoughts that Dr. Fehlings might have about steroids for spinal cord injury.

Dr. Fehlings: Well, there have been very few clinical trials in neurotrauma and even fewer in traumatic spinal cord injury, and very few of the trials have had a positive outcome. One of the few prospective, randomized control trials that had a positive outcome was the NASCIS II, which was published in 1990, in the New England Journal of Medicine.

This trial showed, on a secondary analysis, that patients with traumatic spinal cord injury, who received a 24 hour infusion of the steroid methylprednisolone, had improved outcomes at six months.

When the results of this trial come out, the wave of enthusiasm was remarkable. If one thinks about when new technologies come out, there is initially this enormous wave of enthusiasm, and this occurred.

In fact, as a junior faculty, I recall challenging the senior authors on this paper at an academic conference, perhaps suggesting that they might wish to tone down the exuberantly positive comments on the use of steroids. My remarks I don't think carried a lot of weight at that time.

Then what occurred, for various reasons, medical/legal reasons and a variety of other reasons, there was in essence a professional backlash in that the effect sizes weren't that large. There were potential complications from the use of steroids. Then we saw the downturn in the technology.

What's occurring now is that people are looking at the results, and they're saying, "Well, wait a minute. We don't have a lot of other options for people with traumatic spinal cord injury." The trial was positive, although the effects are small, and we now recognize that there are groups of patients with traumatic spinal cord injuries, such as cervical patients, for whom the impact of a small improvement in function could actually be quite measurable because you might recover hand function, and that patients with a cervical spinal cord injury don't seem to have the same complications with steroids that patients with multi-system trauma might have.

So I think where we are at right now is really in the age of sober reflection, and this isn't really about my opinion or someone else's opinion. This is really about what is in the best interest of the patient and the individual with a traumatic spinal cord injury.

Dr. Hawryluk has been part of this process, so we've had a very thorough, systematic review of the literature, a meta analysis, which was done by a professional statistical group. This was then vetted through a multidisciplinary guidelines group that also included people who actually have a traumatic spinal cord injury.

So, for example, when one was asking, "Well, what is . . . are you willing to accept the certain percentage of complications? Is a certain effects size important? That's quite helpful. In fact, Dr. Hawryluk recently published a paper I think presenting the patients' perspectives on this, which has been quite helpful.

So at the end of the day, we're in 2016, and I actually think it's a bit sad that we are continuing to debate the results of a clinical trial that was done in 1990, that was based on science done in the 1970s and 1980s. Where are all the other clinical trials that are going on, and we need additional clinical trials, because regardless of how we look at this, the effect sizes of steroids are rather small.

The way clinical trials were done in late 1980s, 1990, isn't the way we would do the trials now. We have much better ways that we would do these trials, and frankly we have much better compounds that we can study.

So I think ultimately what is required here is to take a step back to look at this from the perspective of what's best for the patient. To apply the best evidence, but also to intensify our efforts to try find improved treatments.

But the other aspect of this as well, and I alluded to this early in one of my responses, is that I find the attitude when people say that the effect sizes are small as being rather nihilistic. In fact, it recalls moments that I experienced as a trainee and as young attending staff, when I was trying to treat people with these devastating injuries and sort of encountering a lot of negativity.

I think that we have to avoid being excessively exuberant in our enthusiasm when trials come out, but we also have to avoid being excessively nihilistic. The trials are extremely difficult to do, and often there are pearls of wisdom that we might be able to apply for our patients.

Dr. Hawryluk: All right. So the question that I have for Dr. Rubiano is that getting people to choose change is hard. Getting a country to change I would imagine is much harder. I know tomorrow you're going to speak about the things that you have done and the changes that have happened.

How did you manage that part of it, the human behavior, the reluctance to change?

Dr. Rubiano: The key point there we have learned over all these years is how to interact with the human being. I think it's the most complex factor in every process, even in the clinical research.

It's also very important to try to motivate the younger people during training to change minds, because one of our main barriers to implement guidelines and also do research in neurotrauma have been trying to change the idea that there is not too many options for this patients.

We still have in many areas of the world that sense or idea that the neurotrauma patients, our patients who do not have any hope or any possibility. If you teach the same to your students, they will be thinking the same. The key point there is to understand the human behavior, to understand the human being interaction, and try to go over key points to change that.

Dr. Hawryluk: All right I just wanted to ask one last question. I would love to hear from our panelists their thoughts on the future of neurotrauma. So for our senior panelist, what advice would you give the next generation? What are you hopeful of, what advances are you expecting to see? I would be very grateful for your thoughts.

Sir Teasdale: Again I get to start while these guys can think, which assumes I don't think, which might be the case. I think there's two things come to mind.

One is if you take the big picture to recognize there have been dramatic declines in the number of people dying from head injuries. In the U.K., the number of deaths from head injuries have fallen by more than a half in the last few decades from prevention.

The death rate from road traffic accidents goes down, down and down. It's gone down to 20% of what it was, from prevention. The change has been that the traffic accidents have been replaced by falls in older people, which is something important to me of course. It's not only there are more old people, but the old people have fallen more often. But prevention is to get in before the first milliseconds.

Dr. Hawryluk: I want to emphasis the importance of training, and this has been mentioned several times, and this can't be over-emphasized. I think that all of us have been inspired by mentors, and some of us have had the privilege to be able to try to inspire others. I think this is really critical.

But then also in terms of the science, and we can't forget about the science, and I keep hearing about the challenges of trying to link science with medicine, and I'm sure it wasn't any easier when Professor Teasdale was doing it. I can assure you it wasn't very easy when I was doing it. I'm sure it wasn't easy when President Bullock was doing it . . .

Sir Teasdale: There was much less science.

Dr. Hawryluk: . . . and it's not very easy now, and there's a million and one reasons why you can't do something. The trick is to find a way to make it work. We have the opportunity if we think about bioinformatics, big data, imaging, biomarkers, regenerative medicine, if we can actually apply this to neurotrauma and dare to dream the big dream that we can potentially alter the course of people who are horrifically injured with brain and spinal cord injuries.

So I think that the future is bright. I think that this is an area of huge public importance.

Dr. Bullock: If we bring it down back to a local level to what we've seen here in Utah, I've had the privilege to work in three spectacular head injury centers -- Glasgow, Richmond, Virginia, and now Miami. Some of those centers have waxed and waned. Graham and I share a great disappointment that the Glasgow Center was wonderful for about 30 or 40 years, but it's waned.

Maybe now the stimulus could be that you can do the same here in Utah, because you have the leadership that's been behind you here, how to do that. Mike said it excellently. Training, generalization of care, and then hardcore science.

I think the hardcore science now is poised for tremendous advance and excitement. There's a whole area of regenerative medicine which is right now a bit of a clichÈ, but we now at least understand the mechanisms. We understand the roles that stem cells may possibly be able to play in the future and in particular the dangers and pitfalls of being seduced by the wrong message from stem cell based therapies.

So we have to continue to stimulate scientists. There are now in the U.S. well over 1200 PhD scientists in the field of neurotrauma research. That's the greatest that there's ever been. The knowledge base expands exponentially every year.

So I guess the challenge is how to translate that and how to get that into better patient care and better outcomes.

Dr. Rubiano: I just want to do emphasis on two things. One is, as Dr. Fehlings mentioned about the big data analysis, pointing to global neurosurgery aspect, we recently have been into [indecipherable 00:26:37] effort related to improved data collection in specific tracks, and neurotrauma finally has been one of those.

Nearly to 80% of the neurotrauma patients are already settled in low and middle income countries. So we have a lot of data to analyze, and I think improved data collection in all these area will be key for advance in neurotrauma, and also all these multi-centric studies that have been put in place are really, really the future.

We need to analyze all this data and interact within the different context to see if we can teach each other about key aspects that will be really, really important for the future organization, even [indecipherable 00:27:29] and also for the science.

We know for the studies, like for example the [crash] size, when you start analyzing in context and in conjunction data from high income settings and low and middle income settings, you can really collect important aspects of the care. How we'll interact with the outcome of the patient, so I think it will be a key aspect.

Dr. Hawryluk: You can easily see why these are the Neurotrauma Masters. I cannot remember the last time I was in a room full of so much wisdom. I am so grateful that these four individuals have come great distances to be with us as we're opening our Neurotrauma Program. This is a very, very special event. Thank you so much for coming and supporting us.

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