Intracranial Hemorrhage: Advancing Medical & Surgical Treatment Options

Podcast Transcript

Intro: 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: Intracranial hemorrhage is a life-threatening condition, the outcome of which can be improved by skilled surgical and intensive care. However, very few advancements have been made in the field in recent years to progress the prognosis of patients who experience an intracranial hemorrhage.

In today's episodes of Neuro Pathways, we're discussing the way forward for intracranial hemorrhage diagnosis and treatment, with a focus on the collaborative efforts occurring across neovascular specialists. I'm your host, Glen Stevens, DO, PhD, neurologist /neuro-oncologist in Cleveland Clinic’s Neurological Institute. I'm very pleased to have Drs. Bain and Gomes join me for today's conversation. Dr. Bain is a neurosurgeon and head of cerebrovascular and endovascular neurosurgery in Cleveland Clinic's Neurological Institute. Dr. Gomes is a vascular neurologist, neurocritical care specialist and head of the neurointensive care units at Cleveland Clinic. Mark and Joao, welcome to Neuro Pathways.

Mark Bain, MD: Thanks for having us.

Glen Stevens, DO, PhD: My favorite neurologist is the great Canadian, C. Miller Fisher, who, among other contributions, wrote the mechanism of intracranial hemorrhage growth. C. Miller said you learn neurology stroke by stroke. Fisher talked about hemorrhages growing, or the domino or avalanche effect, where one ruptured vessel triggers bleeding into the next. So I'd like to start, or set the stage, for today's discussion by addressing the current state of intracranial hemorrhage. Can each of you address the state of practice in your current field? Dr. Gomes, why don't you go first?

Joao Gomes, MD: Yeah, thank you so much for the invitation. You're correct, and Miller Fisher seminal focused, or was primarily describing patients with pointing hemorrhages based on observations that he made in the pathology lab. And what he described, we nowadays we would call sort of a spot sign that we see on patients early on during ICH. But to address your question, unfortunately, there is not a lot of very specific management, either medical or surgical, for patients with ICH. It's primarily supportive care in the intensive care unit, typically, although that is trying to change a little bit. Blood pressure management seems to be a main focus of medical therapy after ICH. There have been a couple of very important influential trials, both INTERACT-II and ATTAC-II, which looked at different thresholds, or ranges, of blood pressure after an acute ICH and tried to determine outcomes.

Both studies were technically negative, unfortunately. However, some post-hoc analysis show some potential signal in more intensive blood pressure lowering. So a lot of the efforts early on, going to blood pressure control as I mentioned. Then the other big area for medical management has to do with anticoagulation reversal or allopathy reversal in patients who are either on warfarin or some sort of direct 10 inhibitor, which are becoming more common these days. And so a lot of effort also has been put into that, but by and large, most of the hemorrhages that we see are spontaneous, we think related to hypertension or amyloid angiopathy. And as I already mentioned, not very specific treatments available thus far.

Glen Stevens, DO, PhD: So maybe one of the best things we can do is try and prevent the person from having a hemorrhage in the first place. So risk factor modulation. What should we be doing? What would decrease our risk of having a hemorrhage?

Joao Gomes, MD: Yeah, great question. So certainly blood pressure control would be the most important thing that we could tackle. And then other sort of general measures that still I think would be helpful include the reduction of the smoking, improving your overall cardiovascular health, including exercise, would be very helpful as well to try to decrease, but you're right. So prevention is key for this disease. Unfortunately even if you control blood pressure in the population at large, you're still going to have patients that for one reason or another are going to experience an intracranial hemorrhage. So we still need to find effective therapies. I'm happy to talk about the efforts that we have ongoing and where we see the field going in the future.

Glen Stevens, DO, PhD: And Dr. Bain, your thoughts?

Mark Bain, MD: Yeah. Thanks, Dr. Stevens for having me. This is a field that is, I think somewhat of an orphaned field when we talk about stroke as a whole. Intracerebral hemorrhage unfortunately suffers because there's been a couple of trials that were done, that really were negative, and they've had a large impact on how we view and how we treat intracerebral hemorrhage. Those trials are stitch trials. These are large randomized trials that looked at surgery versus medical management for intracerebral hemorrhage. Both of those trials, or stitch one and stitch two, really show that there was no benefit if surgeons like myself went in and operated on these hemorrhages, there was no benefit to functional recovery, and there was no even survival benefits. Our patients were still dying if we operated on patients. So those trials had really stuck with the neurosurgical community and I think the intensive care community.

And because of that, we really have not seen surgery as a valid option for people that are suffering large hemorrhagic strokes, like intracerebral hemorrhage. Now, when you look at other trials, there's other trials throughout the world, and these are some of these are old trials where you look at some potentially minimally invasive or minimal access approaches to removing these hemorrhages. So what that means is that you have a procedure where we use typically small tube-like retractors that we can insert down into the hematoma and remove it. And the thought is, is that the reason those initial trials were negative is we were just creating a ton of collateral damage on the way in, and also when we were removing the hemorrhage, so people weren't getting better. So we're hopeful that some new technologies that have just come out in the past five years or so will allow us to access hematomas in a minimally invasive way and then remove the hematoma so that patients can get functional improvement.

Glen Stevens, DO, PhD: So Dr. Gomes, standard of care, as you've mentioned, has probably not changed a lot over the years. Where do we need to go, medically?

Joao Gomes, MD: Right. You know, speaking of blood pressure control, one of the things that we found when we looked at our own data is that that intensive blood pressure control, overzealous blood pressure control, can actually lead or is associated at least with the development of ischemic strokes, somewhat paradoxically. Initially, we struggled to understand that, but we think that these patients have a vasculopathy, or most of them do, so in that spectrum and that continuum of the vasculopathy, vessels could rupture and lead to ICH. But also if you hypoperfuse acutely abruptly, you can end up with an ischemic stroke. As I said, somewhat paradoxically. Subsequently, in data from those two biggest studies that I mentioned earlier, INTERACT and ATTAC actually showed that blood pressure variability in particular was associated with worse outcomes. So one of the things that we are doing right now, we got a grant to allow us to look at the effect of blood pressure variability using different intravenous antihypertensive agents.

We think that based on pharmacokinetic properties, some of these agents may actually afford a more controlled sort of reduction of blood pressure with less blood pressure variability overall. And we hope that that could be a sort of an avenue for improved outcomes. So we started at the very beginning, just taking two different drugs, comparing the pharmacokinetic properties and in particular, looking at the blood pressure variability of these patients.

The other area that I think is important to mention in blood pressure control, right now, we use a one size fits all approach, which I don't think makes a lot of sense. If you have a small capsular bleed, it's not the same as having a very large, lower ICH. So to that end, we ... Thanks to our advanced multi monitoring program, we're now using cerebral auto regulation guided blood pressure management, and I'm working with one of our fellows who's also similarly working on the grant, to start understanding this process a little bit better and to see whether using a cerebral auto regulation as the guide for the optimal range for blood pressure, may also lead to improved outcomes. And that's just two examples of sort of how medical management may fall with it, in the future.

Glen Stevens, DO, PhD: So with subarachnoid hemorrhage, you can certainly see vasospasm. Do you see that with intracerebral hemorrhage or you don't?

Joao Gomes, MD: Not commonly, and Mark, feel free to comment on that as well.

Mark Bain, MD: And very uncommonly we see vasospasm. Vasospasm with subarachnoid hemorrhage, we usually almost always see it when an aneurysm ruptures, so it's very rare in this patient population.

Glen Stevens, DO, PhD: Is there any role for cooling patients with intracerebral hemorrhage?

Joao Gomes, MD: That's a great question. And the stories that have done so far, relatively small and cooling, as you know, even for cardiac arrest where there is some benefit that has been shown of late, that world has been shaken by, by TTM2 trial, showing that all you need to do is prevent fever. So years ago, with one of our collaborators here, we actually wanted to do a study on normothermia and looking at the inflammatory markers.

I do think that another important medical target is the per hematoma edema development and the secondary injury that happens after an ICH, and we think that a lot of that secondary injury is meditated by inflammation. As you know, fever and temperature modulation do impact the development of the inflammatory response. So I think that there might be a role for that in the future. Although certainly we don't know that data currently. Another effort, and Mark can expand a little bit more on this, that we're doing is trying to characterize what that immunological response looks like in the perihematomal region. So when he goes there and tries to evacuate some of these hematomas, we're collaborating with research at Lerner to try to characterize and understand a little bit better, what the immune response looks like. Mark?

Mark Bain, MD: Yeah. So we are... I feel like we're sort of early in our experience with intracerebral hemorrhage and I think there's a lot that we need to study and a lot we need to do. Currently, I think we are at the point where we're sort of honing our surgical skills. If you look at where ischemic stroke was in 2013, when we had all these negative trials, and doing mechanical thrombectomy and opening up blood vessels for lack of blood flow, or ischemic strokes, that procedure almost died because of negative trials. And then all of a sudden, in 2015, we got better techniques, better devices, and we had better design trials, better selection. And all of a sudden, all these trial are positive and look where we are today. Now we are building whole stroke systems and getting patients to the hospital quicker and having amazing patient outcomes when we're opening blood vessels. Intracerebral hemorrhage is a field I think is sort of where stroke was in 2013, we don't necessarily understand the proper patients to operate on.

We're still sort of honing our techniques surgically, like I said, and as Joao mentioned, we don't truly understand what the inflammatory cascade is around these hematomas, and how can we help patients by stopping inflammation? So I think the next 5 to 10 years in this space are going to be absolutely fascinating. We're working on better devices, like I said. We can even do this through endoscopic approaches where we can make small bur holes, placing these little tubes about as big as a straw down into the hemorrhage, remove the hemorrhage with minimal collateral damage to the surrounding brain. So the hope there is that you can stop pressure on the surrounding neurons and the surrounding white matter tracks. By getting the hematoma out, we can reduce the edema and the swelling reaction that happens and the secondary injury.

And we've even done research, looking at these spot signs. This is active extravasation of contrast on CT scans, suggesting there's active bleeding happening. And we know very well that we leave those alone, those hemorrhages will continue to expand, and most likely the patient outcome will be fatal. And so we've actively targeted those spot signs with our devices and found bleeding vessels that we can coagulate and stop the hematoma from expanding.

So all these, I think are these therapeutic windows where we can potentially interact. The challenge now is, like I said, to hone these skills and to make them standard across practitioners so we can study them. And then we need well-designed randomized trials to prove that this is working. In our experience, and Joao and I have shared patients where we've seen this, with the properly selected patient, in the right time with the right procedure, we've had dramatic results where patients come in, not speaking, paralyzed on one side, we take them to surgery and immediately after surgery, they start talking, their arm starts moving. Two days later, they go home from the hospital. So that type of result is possible. We just have to figure out what the best patient to do this on, who that patient is and how can we select that patient, get them to our hospital quick enough.

Glen Stevens, DO, PhD: So, Mark, maybe you just mentioned it, but how do I identify the person that's at risk to have a progressive hemorrhage? Is it a spot sign? Is it something else? Do we not know enough? How do we know patient A is going to bleed and progress and patient B isn't?

Mark Bain, MD: I think it's all those things, to be honest. I think there's some of it we don't know. It's hard to predict. It makes sense, certainly, if you get a patient early enough in the hemorrhage evolution. For instance, we had a patient that came in within 45 minutes of their hemorrhage, or their symptoms, earlier this week. So if you get somebody that early, all of these hemorrhages are going to expand, right? They're in the process of having the hemorrhage happening. But I think there are certain factors we're looking at that can predict expansion.

Certainly the spot sign phenomena is a well published radiologic sign. I mean, it's just a piece of contrast that you see in the middle of the blood clot in the hematoma, which signifies active extravasation. So depending on how many spot signs, the complexity of them, the size of them, we can pretty much predict that that hemorrhage is going to get bigger. There's all sorts of other signs on CT scans, there's island signs, swirl signs, all these crazy names. But basically they're ways of looking at the hematoma that make the hematoma look unstable, or look like that it has the tendency to expand, but also, Joao and I are sometimes surprised. We don't know who's going to expand. And we think a hematoma is going to be stable. And then, six hours later, you get the CT scan, and it's bigger, or you have a neurological deterioration. So I still think there's some work to be done in that realm.

Glen Stevens, DO, PhD: So somebody comes in, they're on a blood thinner. Stop the blood thinner or reverse it, when can you do surgery on these folks?

Mark Bain, MD: Well, we've been pretty aggressive about trying to push the limit on this because we don't want that hematoma to continually be interacting with the brain. With most blood thinners and with our ability to reverse them and our techniques getting better and better, meaning that we have control of the vasculature, meaning that we have instruments and devices that allow us to coagulate vessels to take care of oozing tissue and things like that, we can actually get in as soon as possible.

So some of the old trials, for instance, the MISTIE trials that are well known, were all negative trials, especially MISTIE III, that was the phase three randomized trial that was just done. They were requiring a six hour stability scan so that people wouldn't run into bleeding during these procedures. And when I think about that, that seems sort of ridiculous to me that you would want to wait six hours, let that hemorrhage sit there, causing pressure, causing damage, and also have the possibility of expanding in those six hours. So, with our current techniques and the surgical technologies we have available now, we are really trying to go hyper acute, meaning as soon as the patient gets in, we take the surgery. So sometimes we're in, even within an hour to four hours, it's been some of our earlier times.

Glen Stevens, DO, PhD: And the development of better and smaller or more surgically friendly devices to get the blood out. You want to expand on that at all?

Mark Bain, MD: Yeah. So we... Again, like I sort of said before, we think that the failure of conventional craniotomy and large open surgery to show any benefit was probably because these were emergent procedures, you made a big incision, big craniotomy, we'd open up the dura and the brain would just sort of herniate out. We would get very hyperemic. And then we would just make an opening where we thought we should go in the brain to get to the hematoma and go through normal brain and remove the hemorrhage. And if you think about that, it's a pretty aggressive, pretty dramatic type of a procedure. The procedures we have now, when we first started doing these, we utilized radiologic imaging with DTI imaging to look at the fiber tracks of the brain.

So instead of just going in, kind of blindly guessing where to go, we would use DTI imaging to look at the white matter tracks of the brain, to pick a trajectory that was friendly to the brain, meaning that we would go parallel to the nerve fibers, so we weren't damaging these fibers. And then the devices that we have now are basically conical retractors, they're tubes, and we can navigate those using imaging software and DTI imaging. So we have a very nice trajectory to get to the hemorrhage. We spare the fiber tracts, and then that's just the access. And then to make things even better, we have resection tools through these things called the myriad, or there's these evacuators, they have little side apertures that have these little cutters on them that we can just very controlled, pull in the hemorrhage and then evacuate the hemorrhage that way.

And so we can almost, very smoothly remove hemorrhage and not just sort of pull it out of the brain in a very sort of dramatic way. So the techniques are getting more and more brain-friendly, and as you said, user friendly, and I think that's going to make the huge difference in outcome. The other thing is that we are getting a much better evacuation rate with these devices, meaning that in the MISTIE trials, there was no question that the more hemorrhage you removed from the brain, the better the patients did. And, if you think about it, if we're only getting 50% of the hemorrhage out, that's probably not good enough. And so these devices that we have now in our experience, we were able to get over 95% evacuation rates, almost on all of our patients. So we're getting the hemorrhage out, we're getting the job done. Now, I think it's time to start studying this.

Glen Stevens, DO, PhD: So looking forward to additional techniques, we're using high frequency focused ultrasound here for lesion ectomies for tremor patients, and we're using low frequency ultrasound to open the blood brain barrier to try and give various medications. And there's been some thought that we could maybe use ultrasound to loosen up the blood clot that's there that could then use one of these devices to suck out the hemorrhage that's there. Thoughts on that? I know it's very early on, but either of you, any comments?

Mark Bain, MD: Yeah. I mean, I can start. One of the harder things about dealing with these blood clots is that they're very heterogeneous. Some of the blood clots are very liquid-like, and some are very thick and adherent to the brain. And so you can imagine, when you're going in in a minimally invasive way with a tube to try to remove this, sometimes it's very difficult to get a full evacuation or potentially traumatic to the brain to get a full evacuation.

So there's some data on this originally, and we kind of looked at that data and then have been doing some just sort of early experiments with some models. But one of the thoughts was, if we could liquefy a hemorrhage using ultrasound, make it more in this liquid state, so that it was easier to evacuate, meaning that we could take... some of the tubes that we're using now are about eight millimeters in diameter, but if we could use something that was like a straw size or even smaller than that, and we could insert that into the brain and be able to fully drain the hematoma, it would be way less traumatic to the brain.

So that's something that we're working on now. We have shown with our system here that we have been able to liquefy hemorrhage, and we can see that both on MRI, and we can also see it when we just open up our little model, and we could see that the blood was clotted, and now it's almost like water consistency. And we've shown that we can drain it with very, very fine tubes. So that would be a really amazing thing. If we could take a patient that came in, stabilize them, bring them down to the MRI, we do the ultrasound, minimally invasively drain that hemorrhage, do an MRI, make sure it's all out and then take them back up to the ICU for Dr. Gomes to work his magic with intensive care treatment.

Glen Stevens, DO, PhD: Dr. Gomes, any experience with this or thoughts?

Joao Gomes, MD: Not as specifically with ultrasound. It certainly makes sense that it's a technique that certainly helps facilitate drainage, and as Mark said, we know from the MISTIE trials, that there seems to be a target, a sweet spot, 15 CCs or less of blood residual after evacuation seem to be associated with a much better outcome. So at least we seem to have a target and hopefully this technology should help us get there. The one thing that I wanted to add though is that there is a significant amount of nihilism surrounding the treatment of these patients and oftentimes poor outcome I think is part or is the consequence of a self-fulfilling prophecy. So it's something that we need to keep in mind, just to give you a quick example, we use an ICH score, it's a clinical score that gives you an idea of what the predicted mortality 30-day mortality is for a population of ICH patients.

It shouldn't be used obviously to an individual patient, but it's done all the time. But what we did, we looked back at the patients that had undergone minimally invasive evacuation of their hematoma. And as a whole, we looked at what the ICHS score was and what the predictive mortality for that cohort was based on the ICHS score, which has been validated in the past. And actually, it performed really poorly after you have hematoma equation by this means, which tells you that I suspect in this patient population at least, we might be giving them and giving the family wrong data as to what the potential outcome is because we're using an ICH score that was derived from a completely different patient cohort. It also exemplifies how removing the mass effect very early on can impact mortality. We know that that mortality benefit is there based on our preliminary experience. Obviously we have to understand a little bit better the effect on functional outcomes, but just a reminder to the listeners that we need to be careful not to be creating self-fulfilling prophecies for this patient population.

Glen Stevens, DO, PhD: Yeah. I think that's a really important point, and I'm glad you brought that up. And it goes back a little bit to what to Dr. Bain had mentioned in terms of the earlier trials that were negative trials, and there wasn't much motion, and then you get a few positive trials and standard of care changes. So I think we all need to be cognizant of that in our different fields. So any last comments on your hopes for the field, other than what we've discussed and how we might advance care for these patients, anything different from what we've discussed so far?

Mark Bain, MD: I'd like to add, there are a couple of important trials right now that are ongoing. So one randomized trial that we're leading enrollment in the nation right now is called the ENRICH trial. It's a randomized trial that has randomized patients with certain size hemorrhages to medical management versus this certain minimally invasive approach. That trial is at I think 273 patients, we need to get to 300. We'll know some outcomes there. That's really going to, I think, guide the next steps, at least from the surgical management side. We're going to learn a lot of lessons from this trial, like we learned lessons from the MISTIE III trials, then I think it'll give us another stepping stone to kind of build similar trials in the future, but that's kind of where we're at from the surgical standpoint.

But I think that we, just as Dr. Gomes said, I think that we need to really look at this disease and take some lessons from the ischemic stroke side. I think this ICH story really mimics the ischemic stroke story. And it's a very similar process. I think there's tissue to save. I think there's acuity. And I think if we just sit back and say, oh yeah, that patient's going to have weakness, that's absolutely the wrong thing to do. We need to be looking at this in a controlled way, doing studies so that we can better serve our patients with this horrible disease.

Joao Gomes, MD: Yeah. From my end, I'm really excited, really curious to see what the future holds for immune modulation to minimize secondary injury. I think that's going to be key. There are some early preliminary trials using drugs like fingolimod, for instance, and even Cox inhibitors that had suggested some potential benefit in outcomes. Now, having a more targeted approach once we understand better what's happening in the hematoma region, I think is going to be key and maybe a significant part of improving outcomes for these patients.

Glen Stevens, DO, PhD: Well, Drs. Bain and Gomes, I'd like to thank you for joining me today. Sounds like very exciting things ahead, really looking forward to see the results of that clinical trial that's coming out. And I'm hoping that it changes how individuals will look at patients that have intracerebral hemorrhage. So I like to thank you very much for joining us today.

Mark Bain, MD: Thank you.

Joao Gomes, MD: Thank you.

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