Our next speaker, likewise, needs little introduction. It's an honor to have Peter Hutchinson from Cambridge with us today, who's going to talk to us about an update on surgical trials. Great. Thanks very much. Thank you to David and Dan for the invitation to talk at this international session. If you could bring the slides up, please. Thanks. Great. Thank you. So if you look at the current status of the multi-center international surgical RCTs in TBI, there's currently four at various stages. There's one trial, the STICH trial, of an internal decompression. This was David Mendeleev's study that showed for intracerebral hematoma. Evacuating this hematoma reduces mortality with a trend towards favorable outcome. The other three studies relate to external decompression or decompressive craniectomy, of which the DECRA study was the first to produce a result indicating really no change in mortality, but a concern in terms of unfavorable outcome in surgical patients. Rescue ICP differed from DECRA in its number thresholds for decompression, timing of decompression, and inclusion criteria, including contusions. And the Rescue ASTH is ongoing. So Rescue ICP, we presented the results last year. So I'm just going to summarize them briefly, but really then give an interpretation of how we're beginning to use these results to try and influence our practice to the benefit of patients. So remember the hypothesis for the Rescue ICP study. This was a secondary decompression when intracranial pressure was not controlled with medical management. And the hypothesis is that using this as a last-tier rescue therapy would improve outcome. So patients were ventilated with a brain injury on an intensive care unit with raised and refractory intracranial pressure at a threshold of 25. They were then randomized into what we called an advanced medical management arm. This included barbiturates. And the other arm of randomization was the surgical management, the decompressive craniectomy. The outcome was the extended Glasgow Outcome Scale. And this is important because it's important to look at the difference in severe disability and this differentiation between the lower and the upper severe disability categories. Somebody who is in lower severe disability is dependent on others for care. These patients are generally in institutions, rehab centers, or nursing homes, whereas upper severe disability patients are independent at home for at least an eight-hour period. The study screened over 2,000 patients and randomized 408. It was a major international effort, 52 centers, 20 countries across the world. And this is a summary of the results. As I said, we presented the main results last year. But this is the key slide. So this was the six-month outcome. On the top bar here, you have patients randomized to the surgical group. And on the bottom bar is the medical group. And you can see the marked reduction in mortality with those randomized to surgery but with an increased rate of the vegetative state, lower severe disability category, but also, importantly, an increased proportion who were the upper severe disability, the independent at home or better. Now, when you move to 12 months, which was a secondary outcome, there are some important changes. The mortality remains highly significantly different. But what you begin to see is the surgical patients are improving, moving up the scale with a higher proportion who are now independent at home or better, the USD. So that was 45% versus 32%. And that is now significant at 12 months. This is all very nice statistics. But what actually does it mean in the real world of clinical practice? And this is what I call the what-if analysis. So this was put together by ourselves and Gordon Murray, the statistician. And quite simply, if you take 100 patients in this situation and you perform a decompressive craniectomy compared to medical treatment, you will save 22 more patients. Of those, five will be in the vegetative state category. Four will be lower severe disability. But 13 will be upper severe disability or better. So there is a spectrum of survival. But at 12 months, it is moving towards this more favorable situation. So how do we interpret this? RescueICP, I think we all agree, provides data that is informative for clinicians and families. There is no doubt that this operation in this context is a life-saving intervention. And the other point we need to remember is that these are some of the most severely injured patients whose ICP was difficult to control. And this is why we dichotomized at this level of upper severe disability deemed as a reasonable outcome threshold. So at six months, it reduced mortality from 49% to 27%. But we do recognize a number of the patients were likely to be dependent. At 12 months, the surgical patients continued to improve. So 45% were at least independent at home versus 32% in the medical group. And as I said, just remember for every 100 patients treated, 22 more survivors. 59% were at least independent at home. But there are patients who are generated in the vegetative and lower severe disability categories. And we need to be conscious of that. So what are the take-home messages as we stand with RescueICP? In my mind, there is a place for this operation in the context of TBI. I think that is beyond doubt. But the choice to provide this operation has to be individualized. And we currently need to continue to address the challenge of identifying those patients who are most likely to benefit. And that will involve further studies looking at the physiology after decompression and how we can modify the treatment. One of my theories about why the patients improved between 6 and 12 months in UK practice, this is where many of the patients underwent their cranioplasty. And it may be we should be doing that earlier. So we need to refine the cranioplasty timing and technique. And we have just commenced the UK cranioplasty registry piloted in seven centers in order to look at the timing material of cranioplasty with the possibility of proceeding to a randomized trial. So how can we actually improve decision making? Well, we all know that CT is the first line. It's the gold standard. It is fantastic for imaging hematomas. But actually, should we be looking beyond that? What is important is not to decompress patients whose pathology determines their outcome other than their problem with raised intracranial pressure. And I know that some of these patients, when you look back and subsequently, an MRI scan will show significant brain stem pathology not seen on a CT scan. These are the sorts of patients that may be ending up in the vegetative state, lower severe disability. And we need to think carefully about, is this the right patient to decompress? Likewise, Tony mentioned the young patient with the GCS of four, maybe very bad diffuse axonal injury, not really seen on a CT. Is this the sort of patient we need to think about? So I think RescueICP is trying to make us think critically. And it is not a panacea. We cannot decompress everybody. We need to target those that we think are going to get into those better outcome categories. So what do we do now when we talk to families? So there's information that helps discussions. Historically, in traumatic brain injury trials, we talked about favorable and unfavorable outcome. I think we need to abolish these terms. They're loaded. And what we should do is try and think differently. What is favorable for one family may not be favorable for another. And perhaps better to say that we have the evidence that decompression, this was DECRA before other treatment options, probably didn't help. But as a rescue, where most interventions have failed, it reduces mortality. 40% of survivors are dependent. But 60% are independent at home or better. And it can take a long year. Historically, in TBI trials, we've looked at six months. If we just looked at six months for RescueICP, that is very different to 12 months and beyond. More data. So we've got quite a large series now of patients in who we have quality of life measurements. This is a series beyond RescueICP. And what this shows, in summary, is that the quality of life on an SF36 questionnaire is actually very similar. There is no significant difference between quality of life in those who are scoring a lower moderate disability versus an upper severe disability. So again, probably need to think of other outcome measures beyond the extended Glasgow outcome score. Martin Smith was the chairman of the data monitoring committee for RescueICP. And he wrote this very, very useful sentence. And it came out in Anesthesia Analgesia last year. And what Martin said was, decisions to recommend decompressive craniotomy must always be made not only in the context of its clinical indications, but also after consideration of an individual patient preferences and quality of life expectations. And I think that's a really important statement. I just want to finish by talking about, so this is the primary decompressive craniotomy study. So with an acute subdural hematoma, we would agree that that needs to be evacuated. But there is a decision towards the end of that operation. Do you leave the bone flap out? Or do you replace the bone flap? And this is a trial that is ongoing, a randomization of decompressive craniotomy versus craniotomy. Seeks to answer this question. Does decompressive craniotomy lead to a better functional outcome compared to craniotomy? So replacing the flap for adult head injury patients undergoing an evacuation of an acute subdural hematoma. So it is a randomization, hematoma evacuated, you leave the bone out, or you put the bone back. It includes adult head injury patients over the age of 16 years. In the UK, we have a waiver of consent because these patients lack capacity, and often their relatives cannot be located. The randomization occurs once the hematoma is evacuated, put the bone flap back, or leave the bone flap out. That is web randomization, or telephone, per-operatively. We recognize there are some patients with pronounced brain swelling, not possible to randomize them, so they go in what's called the observational cohort. So again, this is an international study. 28 UK centers, increasing number of international centers. Top recruiter currently is a high-quality center in India, that's Bangalore. And then we have four UK centers, Delhi, and a number of other centers, and increasing interest in the US, and delighted to say that Beth Israel Deaconess Martina Stippler has now randomized two patients in this study. These studies are difficult. There's a lot of issues in terms of protocol approvals, IRB approvals, and this is the recruitment curve for rescue acute subdural. Blue is our predicted recruitment rate. The green is the number of centers on board, and the red is the actual recruitment rate. And you can see at the beginning, when we opened the UK centers, we were on target. At this point, we fall behind, because we can't get enough international centers for various contract reasons. We then bring the international centers on board, and you can see that the recruitment rate has now picked up. Finally, the way these study work in the UK is tremendous credit to the neurosurgical residents. They have set up this trainee collaborative, and this is very much a study that is driven by the neurosurgical residents. They are the ones that are operating on these patients. So to finish, the STICH study showed that early surgery for traumatic ICH reduces mortality with a trend towards increasing favorable outcome. DECRA, slightly controversial as we know, showed that secondary decompression for diffuse injury with this threshold, no difference in mortality and increased unfavorable outcome. With rescue ICP at 12 months, you are generating increasing numbers of patients with upper-sphere disability, independent to home or better. Rescue STH is ongoing. We convened the Decompressive Craniotomy Consensus in Cambridge last year. David came, Dan came, Franco, Tony, and thanks to many people, that manuscript is in preparation and will be disseminated to the contributors to the consensus soon, with a view to publish it, giving guidance later on this year. We've talked about the lower-middle-income countries already. These trials are important, and we really need to see how we can take this forwards in these countries, and the UK government have given substantial funding for what we call the NIHR Global Health Research Group in neurotrauma, and that will include a global neurotrauma registry where we can get a feel for better treatments that are available to these patients and see how we can actually take forward some RCTs to make this a truly global operation. I'd like to thank many funders, particularly the NIHR. The NIHR is 2% of UK health budget now. It's protected. It's just had its 10th birthday and has put a lot of money into neurosurgical trials. That's my email address. If anybody is interested in joining Rescue ASTH, we would very much welcome or send to us. That's the website, that's my email, and these are some of the social media contacts. Thanks for the invitation. Thank you. Questions? Have you had a chance to take a look at two-year outcomes from the rescue ICP cohort? So we have that data, and I think we'll have about two to three months we'll be able to put that out with the consensus, yeah. But DECRA, interesting, I haven't seen the DECRA beyond six months either. No. I don't know what it actually, I suspect that there may be a few more gains between 12 and 24 months. I'm not sure, but we need to look. We have a paper in review right now where we looked at our own institution's performance over seven years, and we tracked everybody out to two years. And 73% of survivors who were labeled as a poor outcome at three months had converted to a good outcome by two years. Seventy-three percent of the poor outcomes. And it comes back to something that you said very quickly, but I think actually has a huge impact in the way that we look at these things, is that we stick to a random arbitrary six-month outcome time point in our clinical trials. And we may actually be losing signal over and over and over again because the recovery curve from this is actually longer than six months. So if you had a change in your thinking, the more that you get exposed to what the longer-term outcomes genuinely are. So there's two points. The first is that the primary outcome measure for rescue acute subdural will be 12 months and not six months. The second is that rescue ICP people were very patient and it took many years. So some of these patients are now eight or even nine years out and we will go back now with new ethical approval and actually look at what life is like many years down the line. And I think your point about that 73% is absolutely critical. Other questions? Have any of you seen an evolution at home in the frequency with which decompressive craniectomy is used now versus five years ago? What's changed? More of it. And you are where? Arizona. Yeah. Anyone else? How many people are performing this procedure more frequently now than five years ago? And what about less? Franco. Franco. Franco, it is not a panacea. Yeah, that's interesting. Tony wants to. As I visit various places, my impression is that the global gestalt is a tendency towards more and not less. And sure, there are patients that won't benefit from anything that we do. But I see decompressive craniectomy as being a critical, critical piece of the armamentarium. Tony, did you want to say something? Yeah, I think I just wanted to say that congratulations. I'm so proud of you guys. You're really leading the way in enabling perspective research in a way that's enormously difficult. But I think, and I'm sure David will agree upon this, that this probably represents the worst case scenario of decompressive craniectomy that we've discussed. Because I think the real world scenario is much better than the results of the rescue trial we suggest. And that being because of the crossover of the incentive and the commitment to not doing any, to do any intention to treat analysis. So you're losing that potential benefit. And if we truly randomize patients to no craniectomy at all, regardless of every circumstance, I'm pretty sure that the distinction between those two groups would be a lot better. I mean, I think we generally do better in terms of our decision-making about who goes to craniectomy. As I was saying earlier, so a 70-year-old patient in GCS4 at the C with a midbrain contusion, even though you'd be eligible for the trial, is not the kind of patient that we'd be offering. We'd be much more aggressive about younger patients with a deteriorating level of consciousness, not due to the primary injury, but because of the secondary effect of isopenia. So I think the real-world applications would take these results and amplify them. So the PERP protocol analysis, we can do with the two years. But I do think that CT is missing an awful lot of pathology that is absolutely critical. And we need to try and think a little bit wiser about how we can get early MRs in these patients. OK. Thank you. Great. Thanks very much.

surgical trials

rescue ICP study

decompressive craniectomy

mortality reduction

neurotrauma