We're going to go ahead and get started here. So to wake you guys up here I have a special treat. Dr. Bell, Commander Bell from Walter Reed who is actually going to show you sort of the extreme application of anti-coagulation and heparanoids in the use of patients with penetrating brain trauma. And in terms of the dogma, I was the dogma. I was a true non-believer. I was the guy who was most concerned about stirring up hemorrhages in all of our penetrating brain injury patients as they were coming back from overseas with the anti-coagulation. And his analysis of the data has really opened up my mind. So we'll go ahead and start with Randy's presentation here. And then we're going to follow with going back and comparing this to the guidelines as well. So just to clarify, this is chemoprophylaxis, not quite anti-coagulation yet. So yeah, I work at Walter Reed. I've been in the military since 2002. I studied under Rocco. And this was a unique problem, as I'll explain, that is sort of, it has brought to light some interesting questions. And hopefully I'll challenge you guys to think about this in a different way. So we'll just go through sort of a brief background, foundation. I think Dr. Ullman later on is going to go through the guidelines in a little bit more detail. So I'm not going to go through a lot of these existing study. I'm going to talk to you a little bit about our pilot study results, why this happened, why we were actually kind of forced to do this study in the military questions. And then I'm not going to spend a whole lot of time talking about the research that I'm doing right now. But I will just sort of let you know kind of where things are going and why I think it's important to ask the questions. So this was a 27-year-old special operator. And he was in downrange Afghanistan. This is a penetrating brain injury. This is what they typically look like for us. This is a blast penetrating brain injury. You can see to the left there's a fragment near the interhemispheric fissure. You can actually see him post decompression because, I mean, in the military with penetrating brain injury, if you're going to do something for folks, you do it right away. You go big or you go home. You can see a lot of the other fragments. There's some indriven skull fragments as well. This is day of injury. And then this is just another cut, again, indriven bone. And you can see there's also a fragment in the cerebellum. He actually had multiple penetrating fragments over the right side of his body, both supra and infratentorial penetration. Post injury day 2, everything looks just fine. Post injury day 4. Now, not seeing post injury day 4, how many people would give just DVT prophylaxis within the first 12 hours of injury? 24 hours? One for 12? 24 hours for penetrating brain? 48 hours? Okay. So folks start to get a little bit more comfortable as time goes on. This was four days after. Okay. So, and in this patient, I'll let you know whether or not he got chemical DVT prophylaxis or not later on as we revisit. So this is a second case. This is another mid-20s year old active duty Marine. This also, this was actually an injury that was sustained in Iraq. This is a penetrating facial injury, but you can see that the fragment actually hit his middle cranial fossa, bounced off, went through his orbit, took out the eye and then resulted in this more of a contusion type pattern in the brain. This was day 1, day 2, day 4. How many people would have started some DVT prophylaxis within the first 12 to 24 hours? 48 hours? I'm sure if I go out, folks would be much more comfortable. You can see that over time, oh, I'm sorry, 48 hours? Amy? Okay. Got it. So you can see over time that the hemorrhage itself actually starts to get a little bit bigger, you know, and it's not unsurprising. Even contusions sometimes will expand within the first 24 hours. You can also see the edema pattern surrounding it with a ventriculostomy and starts to get more prominent and significant midline shift by day 4. So at the time, so over 13 years of conflict, as you guys know, majority of the casualties, we took care of it, Walter Reed, based on the Aravac pattern, which I'll describe to you in a minute, in a little bit. And obviously, we've published extensively over the care of penetrating brain injury with unprecedented survival and with that unprecedented survival from the battlefield comes unique challenges that, you know, would not have been there if, as in previous conflicts, these patients were treated expectantly or left to manage on their own. Don't need to talk to this group at all about secondary brain injury. That's kind of why we exist. Not much we can do about the primary. And so when we first studied this, Rocco and I, in 2008, we looked at our first 408 neurosurgery consults, I guess, that had come back to Walter Reed from the conflict. This is sort of the descriptive constellation of what we saw in that group. And you'll notice in red that pulmonary embolism rate of 6.8%. That's kind of a huge number if you look at it in relative comparison to, for example, the Pennsylvania trauma database where over several hundred thousand patients in that database and a DVT pulmonary embolism rate of about 0.5%, give or take. Again, I'm not going to go over this too much, but we know that traumatic brain injury independently associated with DVT in multiple studies, up to a third of moderate severe TBI is comorbid with DVT. Seven percent of our casualty had comorbid pulmonary, our combat-related TBI pulmonary embolism. And increasingly severe TBI probably correlates with increasing rate of both DVT and PE. Again, I'm not going to go over this too much. I will point out there is at least one prospective randomized trial that looked at this in closed head injury. That's the DEEP-1 trial. I think that this trial actually focused on closed head injury with cerebral contusions of 20 milliliters or less. And it was a positive study that basically showed that cerebral contusion does not increase in size when you start DVT prophylaxis early. And then we looked at the TBI. So what's the problem? I think there is almost everything about this in trauma in general, certainly penetrating brain injury that we don't know. When is it appropriate to start VTC and TBI? What's the appropriate agent to use? Should we be using heparin? Should we be using Lovenox or any of these other new, probably not these new devil agents, the 10As and the two inhibitors? You know, is it appropriate to use in TBI and why? And then obviously the other questions. The other one I asked lastly, are heparinoids neuroprotective? Turns out in many animal models they are. They're both anti-inflammatory and neuroprotective. So the reason that I was able to study this, and I'm kind of thankful about this, is that we are the problem in this. For the last 80 years or more, I think the gut feeling for many in trauma is I don't want to see a hemorrhagic expansion. I don't want to do anything to cause that to happen. And I think because that was our gut, there wasn't a lot of meaningful study in this area relative to some of the other areas in neurosurgery. And so this whole area is ripe for both study and thankfully funding, which is great. I think we're all relatively reluctant and that actually makes it a good thing. So that pulmonary embolism rate of 28 patients out of 408, 6.8%, why is that happening? For us it's a unique problem, I would say. Probably not so much for you all in the civilian sector, but for us it is. So I deployed to Kandahar, Afghanistan in 2013. I was there for a year. Patients would arrive to us usually on day of injury within a couple hours of their injury. If they needed surgery, we did it immediately. Stabilized them. And what we needed to do was then actually get them ready for a long transport in a C-17, right? Pressurized cabin pressure at 10,000 feet, 8 to 10,000 feet. They got to go from Kandahar to Bagram, which is about a two and a half hour flight north in the Hindu Kush. They get checked again, put back on the plane, and then they got to go to Landstuhl in Germany. That's about an eight hour flight. During this entire time, obviously, if they're a severe penetrating brain injury, they may or should have at least some form of ICP monitoring, usually a ventriculostomy. There is no neurosurgeon on this flight. All of the details you have to remember, like, you know, simple ones, like make sure that the head of the patient is towards the front of the plane, because when the plane takes off, they're going essentially reverse Trendelenburg. That's what you want, right? The rest of the time they're flat, right? And then from Landstuhl they come back to us at Walter Reed. That's usually, at the fastest we were able to get folks from the battlefield to us was usually about 36 hours, which if you think about a worldwide trauma evacuation system is pretty good. But still they're flat the whole time with agents to keep them sedated. No venous tone whatsoever. All right. Again, I won't go over this at all. So what I didn't know at the time I got to Kandahar was that as soon as the patients left my ICU, our trauma surgeons were actually starting them on Lovenox. They get to the plane, the C-CAT, combat casualty care mission, and then they would get some form of DV, usually 40 milligram sub-Q, right? And so when I found out about it, I basically had to ask the question, okay, what the heck is happening here? And this is what we did. This paper was published, I think, in 2017. And what we looked at was whether or not it was safe to actually do what we'd already done in a retrospective fashion. And we used as our primary outcome measures worsening intracranial hemorrhage and then did giving chemical DVT prophylaxis in these patients actually affect in any way meaningfully the rate of deep vein thrombosis and pulmonary embolism. You can see all of the secondary outcome measures. These are standard trauma outcome measures, but also for us things that were relatively unique that we've been studying for many years and wanted to collect as well. Secondary to this, we actually also looked at exposures to pro thrombotic medications, and there weren't as many at this time point. But for years, you may recall that folks were getting factor VII downrange relatively liberally. There were considerable problems with that. We stopped that practice. And then with crash one and crash two, and I think now crash three underway, the use of TXA and trauma has become completely ubiquitous for us. And it's something I would ask you guys to consider doing as well. So this is what we saw over a three-year period. The vast majority of what we saw downrange were injured Afghanis. And so that's the hard part, right? How can you get follow-up? Well, we don't have them. Once they left our hospital, they went to the Afghan system, and sadly, we never saw them again. And we were left with, in our cohort from those consults, 67 patients that were U.S. servicemen or women that I could follow in our electronic medical record system out several years. And so this is the basic demographic data. You can see there's not a whole lot of difference between those who received early BTC and those who did not. Now, for not having any way to prospectively plan this, the data cohorts actually worked out and matched pretty well. Obviously, age is going to be young. This is, as with the civilian sector and the military, trauma is a problem that is vastly towards the male side of the house. We do have problems studying females and trauma. That's been pointed out. I don't know if you guys, there was an article recently Odette Harris wrote on this exact subject. But nevertheless, 35 and 32, I think this number of patients actually sort of looks at and does adequately describe the equipoise that we sort of see in this area. Presenting intracranial pathology, while there was no strict association between different types of intracranial hemorrhage and whether or not there was an effect with early BTC, you can see there was a trend with subarachnoid hemorrhage. There was a trend with subdural hematoma. But take a look at where the numbers fell. More subarachnoid hemorrhage and subdural hematoma in those who did not get BTC as opposed to those who did. Interesting. Totally observational. So this is what the results showed. And again, there was not any true, strict statistical significance. But what it does show is that there was, at least as far as DVT and PE is concerned, a trend towards a reduction descriptively in DVTs and PEs. You can see the overall rate super high at 15%. But fewer DVT, PE in those who received and those who did not. Subsequent analysis showed that the number you need to treat in order to prevent one venous thromboembolic event in a patient with penetrating brain injury is 22. So intracranial hemorrhages, overall incident, I'm sorry, overall there were 15 worse intracranial hemorrhages, four with incremental changes in their lesions prior to exposure to VTC. You can see that there were 11 incident worse intracranial hemorrhages, six in those who did not receive VTC, five in those who did. And by the way, I should point out that Lovenox was almost ubiquitously the agent of choice in this. Yeah. What is your definition of early? Oh, I'm sorry. Forgot to mention that. Average time to first dose was less than 24 hours. Less than 24 is zero. That's correct. Yep. Forgot to mention that. Is that after a second dose? So I'm going to talk about that, but yes, without question. And I think that's important to point out. Okay. So we already knew that DVT-PE was a significant problem in our particular population. There's many hypothesized reasons. And it is very consistent with past studies that we have done. And then, you know, again, I've already talked to you about what other databases have shown. This obviously is a retrospective observational study design. There's inherent selection bias. This is a relatively young, healthy military population. That being said, trauma in general is a young population, although the healthy part, I think, is a little bit different in the civilian sector. And again, these results strictly apply to this cohort, but I think with respect to penetrating brain injury in general, I think it has broader application. It's also a small study, but I would also challenge you to find a study that has 65 survivors of penetrating brain injury in a three-year period. It would be tough to do unless you use multiple sites. So this is what we concluded. It was both safe to do in this population, thankfully, in hindsight. And then there might have been a trend towards reduction in DVTs and PEs. So I show this case again because this is something you need to look out for. This was four days after injury. I think you may remember this case. This is why he was actually on a plane from L'Ange d'Oule to Walter Reed when he had alteration in, I think, did he have a ventric at that time? He did not. Alteration in level of consciousness a little bit as they were doing neurochecks en route, and this is why. So he basically, around that fragment, had a delayed hemorrhage at four days. And if you can see on the angiogram, which I did the day he arrived, there is a small pseudoaneurysm in the A4 segment adjacent to right next to that fragment. And this is something that we've been looking at for years, building on the work that Bijan Araby did from the Iran-Iraq War in the 1980s. Any penetrating brain injury, I will tell you, probably needs a cerebral angiogram at some point in time. And it's something that you really need to think about. I mean, there's beam hardening artifact there that you can see on CT scan. It's going to not allow you to see with CTA, and so it's something to consider. You can see a little bit closer. This is an oblique view. And then basically, just ran a little marathon microcatheter out there, injected a little onyx, and it's done. And so after that, subsequently reconstructed him, and it's fine. You can see the little onyx cast right there. And so to your point, Dr. Ullman, there are a few things that you really need to be sure of before you consider doing this. A stability CT scan is absolutely critical, I think, depending on what you would consider. Generally, we had them for at least 24 hours. And so, you know, at the 6 and 12 hour point before they got on the plane, we could generally speaking scan them. And that was I think the case. So this patient was subsequently decompressed, mainly secondary to increased elevation and ICP and midline shift. This patient did not receive any chemical DVT prophylaxis throughout their entire first week of care. So, yeah, we went over that already. So when we did the study, we started publishing, I started thinking, what if we're actually hurting patients by not starting chemical prophylaxis earlier? What if heparanoids in general reduce the extent of brain injury? And there's a couple of different hypotheses about this, you know, I thought might be appropriate. And this is kind of where we're going. Most of my studies have just started within the last year. And so we're working in multiple different animal models. There's a penetrating close head injury model in rats. We're moving to ferrets now, in case you've started. If you haven't, you do neurotrauma research and you're applying for grant funding, the move from non-gyroencephalic to gyroencephalic model seems to be apropos right now. I don't necessarily know if it's going to make a difference in translational research, but these are what we're looking at. These are the questions we're looking to answer right now. Do these pilot study conclusions apply to our entire population? So I've got a database study looking back to 2003, 6,500 total moderate to severe brain injuries, and we're just going to look at the entire population and describe the change in use over time to see if there are any additional correlations. Is there a different response in early BTC between patients with close and penetrating brain injury? I think that's important to look at. What's happening in the microvascular cellular level? What is the current agent dose timing? One of the things that we're going to do early on is look at the pharmacology of heparanoids in both close and penetrating brain injuries, see if we can identify a sort of LD 50 for hemorrhagic expansion in our animal models. At what dose can I guarantee that at least 50% of the animals will have hemorrhagic expansion and to what extent? There are ways to translate those data to humans as well. So this is what we're doing. It's a sort of a multi-tiered both clinical and translational research effort. And I guess, you know, when we looked at it, these are the possible mechanisms that are defined in the literature. You know, is this an issue of plumbing? If you get an intracranial hemorrhage or edema, I mean, arterial tone is probably going to be preserved, but venous tone may not be. And this could be simple outflow obstruction with pooling of blood and veins and giving a little bit of VTC might actually help reduce the edema. Does heparins have been shown to reduce leukocyte egress? The mechanism you can see right there. And then possibly intracellular calcium release, which might or might not be neuroprotective. We'll take a look at all of them. Okay. That I think is where I want to leave that. I guess the whole point I would say, I'm sorry, I'll, yeah. Yeah. So it's simply the location and where we're at. I mean, I think that without question, you could have put, I certainly could have put coils in that. It's far enough distal. I don't need to preserve the parent artery at all. A4, A5, given the extent of surrounding brain injury. When I inject glue, I know it's out. It's done. I mean, with coils, sometimes it takes a little time for thrombus. You don't know. There's also the risk of coil perforation, which is a little bit lower than when you're using. And you remember with these traumatic aneurysms, these are not true saccular aneurysms, right? This is essentially a blood clot, right? And so the less you can access that, we have coiled many traumatic aneurysms certainly, but given where it was, I just decided to cut the blood flow off and leave it there. So, yeah. So, I have a quick intuition as to the, keep increasing the help for 48 hours. Do you hold it? Yeah. And so that's, there are some, that is precisely what we do. We definitely get a stability scan. Would not start, I would personally not recommend starting in trauma period any VTC, any chemical DVT prophylaxis prior to at least a 6 to 12 hour scan where you have proven that the clot, whatever it is, is stable in size. I don't know that it's terribly defensible. You do have to rule out arterial, traumatic arterial, and sometimes venous injury in the best way that you can. I would recommend that. Those are sort of the main areas that are, that's important to consider, so. These are great questions. So, what we'll do is go on the next presentation.

anti-coagulation

penetrating brain trauma

chemical DVT prophylaxis

reduction

ongoing research

brain injury