Transcript Video What's Next < Back to Summit23 Brain Injury Management What's Next Presented by Associate Professor Per Nordberg And now it's my pleasure to introduce Per Norberg. Per Norberg is a very outgoing guy, very easy going, but he's also a special guy. He works at the Carolina Institute in Sweden Stockholm. So a great place and he is uh working for the Department of Clinical Science Interventional and Technology. He also works clinically not only on intervention, but he's focused on studies on hypothermia. So he was the principal investigator for the Princess trial. And you heard that mentioning several times during this day uh these days and he was involved in att M one and TT M two. So an excellent speaker to discuss what's waiting for us tomorrow or the day after tomorrow in the in terms of studies and then on the clinical arena, please be. Thank you so much. Thank you so much for the presentation and thank you for the invitation to the meeting, Christian, very important meeting and very inspiring meeting. And um I will try to talk a little bit about what's next. And um basically from a research point of view, I will talk about some ongoing studies, uh very interesting and also upcoming studies. So I would basically focus on, on um, three main studies. And then I got a synopsis yesterday at about 7 p.m. I started that I didn't have time to put in the, the slides, but maybe I can discuss it a little bit in the end. So, uh I will talk, they are, these are three randomized control trials and, and, and, um, with, with three completely different concepts. So, so first is the, the ice cap trial, that's the US trial started in, I think 24,019. And it's, it's uh it's very interesting. It has a completely different starting point than most other trials. It's as the starting point that hypothermia is effective and it's all about finding how to clinically apply it regarding the dose, uh which is basically the duration of hypothermia and also early cooling in a bit. So I will talk a little bit about that and then I will talk about uh the upcoming step care. I think it's just started uh in a couple of sites in Sweden. It has three arm study with, with one is about temperature control and the starting point there is, I, I would say that TT M in card is not uh you don't have to do it. So that's, that's um their starting point. And then our starting point in, in, in Princess, in the Princess network in Princess two is that you have to apply it according to the pathophysiology at a very early stage to be effective. OK, let's start with ice cap and its influence of cooling duration on efficacy in cardiac arrest patients. This basically, it it's doing the same study. But in two different populations, they will do it on shock of rhythms and non shock the rhythms, they will do exactly the same intervention in the two patient groups. OK. They have 33 research questions. Can the duration of hypothermia improve patient outcomes? That we talked a little bit about that yesterday. And Fabio and colleagues have done the, the 2448 study. And also can you can the efic of hypothermia be confirmed by evaluating duration response and then also uh in in relation to patient uh safety and, and uh patient reported outcomes. Um OK, uh which patients do they want to include an ice cap? Well, it's quite similar to, to most of the trials. It's comatose patients after out of hospital cardiac arrest. Um They have this is this is I think this is a more narrow window than most of the trial. The patient has to be cooled down to 34 degrees within four hours of the rest to be able to be included in this time. So it has to be some kind of, you know, you have to start cooling at the earliest, early time point to be down to th below 34 degrees. So you have to have a definitive temperature control applied adult patients and then there's um consent, consent issues and so on. And then the exclusion criteria is pretty similar and dynamic instability and so on and so on. So it's so it's a pretty straightforward with a, with a patient and then it's a little bit, it's a little bit complexed for me as a pragmatic researchers, they, they randomize uh into three group in the first phase, the two first 100 patients. So 12 hours, hypothermia 24 hours or 48 48 hours. And then after that, they have a adaptive design. So they can, they can basically see where you have the signal. Is it more beneficial for the patients to go to 48 than to 24 often 24 to 12 hours. And then you can adapt, you mean you can, you can uh push more patient into the group where you seem to have the most effect. Uh And um if you don't have an effect, if you don't see any effect, they have several of these interim analysis, you can, you can stop the trial at an early stage. So this looks a little bit like this. Uh So first you have three groups and then as the studies keep on going, you can adapt. So you find the right dose, these are many, many groups. But at first, you just have three and you just open up for the longer duration. If you see a signal towards more efficacy in the long duration, right. So you have an updated adaptive design after about each 50 patients. So it's, it's a computerized, of course. And uh and uh I don't know exactly how they do it, but that's, that's, that's their way to try to find the right dose. And they will look at the modified ranking scale at 90 days uh as a primary and also, of course, all cause mortality and the patient reported outcomes. So that's uh uh basically what I have to say now about the ice cap ongoing. It's been randomized 830 patients. Uh And the goal is to randomize 1800 patients. So it's a big trial. They're almost halfway. Um OK, let's move over to the step care. The step care is my colleagues in down L TT M group. Um They continue with this trial. Um and it's a three armed interventional trial. So uh it's both about sedation. One part is about temperature and the third part is about finding the right uh military pressure that brun talked a little bit about. And uh it's uh so basically the patients that go into this study are randomized three times into three different interventions. So what's what's about temperature here is the temperature arm where you, you um you look at fever management with or without a feedback control device. So basically put on a be proactive or reactive, but without the device and the other arm are continued sedation for 36 hours, you know, standardized or minimal sedation where you as little as possible and wake up the patient as early as possible. And the third arm is mean material pressure, two different targets a little bit more separated than the Danish study that came out the, the, the, the a year ago. Um, ok, so they have basically the same patients comatose patients with sustained risk and uh should have any restrictions in intensive care. And you have an enrollment window which is similar to the previous trial is quite wide and you start the intervention at quite late stage, um, very heterogeneous population, very big population and uh the exclusion criteria. Sorry, it shouldn't be on ECMO pri no E CPR patient and pregnancy of course. And um, if you have a suspected or confirmed ble bleeding in your head or uh if you have been prior randomization in step care. Ok. So I think this is a very interesting from a statistical point of view. So the patients can be, can be going into eight different groups with a different mix of blood pressure targets, TT M targets and sedation targets. And it's, I think it's, you can do this type of trial, but you also have to be aware of that could be a uh interaction in the therapies. You know, the sedation affects your blood pressure. Um, and also the, the, the, the, the potential fever if you're sedated or not. So it's, it's a lot about a mixture and trying to manage the patient by the strict protocol. So it might be some difficulties here, but it's, we will see along the way, some of you are probably involved in the study. Um So basically the one group have a, they have a device and uh you monitor the temperature and if the temperature is going up, you just put up, put on the device. If you approach uh the limit of 37.7 um you do this for 72 hours and the other no device group, uh you monitor the temperature and then you treat fever as any other IC U patient, which is probably different for all of you. How you, how you do it, some of you put on the device directly. So that's not really allowed in the no device group. So you have to um this is a little bit unclear, you know, and it's a lot about, you know, leaving it to local protocols uh which may be a weakness of the, of the design. OK? And they have mortality at six months as a primary outcome. They will also look at modified ranking scale and, and uh and the patient reported outcome. So it's, it's um it's a complex trial as well with three different integration. And uh we'll see, you know, I 34 years how it turned out, I would say uh OK, now we'll talk a little bit more about and a little bit more in detail about the, the what I'm working with a lot. The Princess two trial and the concept of, of early cooling. We have been working with uh network for quite a long some time now or more than 10 years with the concept that you have to be, you have to start very early to have an effect of hypothermia to have the best possible effect of hypothermia. We know that the effect. We talked a lot about this yesterday. We know that the effect is, is much, much greater in, in, in the earlier, you can come into the course of treatment if you can do it in the ischemia phase or at just at the the risk that's much better probably than to go late. We know that the TT M trials started very, very late three hours after the cardiac arrest itself. So it's with and probably with insufficient methods to really cool down the patient at an early stage. So that's, that's our concept. Um And we have used a method which called transnasal evaporative cooling. It's very easy to use. You can apply it. We have studied both pre hospital and the emergency room with the cat lab. It's very easy to apply. You have some nasal prongs, you just put it in and then you turn on the machine, it delivers a mixture of of oxygen and liquid coolant. They cool it very rapidly in the nasal cavity and it cools the brain primarily. And I think that the two bullets, the last bullets are very important. This can bring continuous cooling to the patients. You know, when you're just, we talked a little bit about Christian, talks a little bit about the pre hospitals. Tries with IV fluids. You can cool down very rapidly when you stop the infusion, the patients rearm and rearm quite fast. And we know that this is probably not good for the patients. And the other thing is the volume load. It's also the pre hospitals trial, especially the Rins trial with when they put 2 L of intravenous fluid in patients with ventricular fibrillations, they had a significant lower ro grades. That's not, you know, for me, that's not so strange with you have a acute myocardial infarction and you give them 2 L of fluid during the correct arrest. That's we know that's not good. So you can call the patients, but it's from the h dynamic point of view, it's not good. So this method has some advantages to, to, to, to cold fluids. Ok? And this is a film, it's not so good quality, but it shows how you do it. You put in the nasal prongs and uh in the nasal cavity, you see that delivers the the mixture of, of coolant and oxygen and it cools during CPR D con conductivity. And then when you have the ros you will also cool the vessels going up to the brain. So you have some kind of uh gradient uh cooling from the brain and then the rest of the body. So this is the concept of transnasal evaporative cooling and you cool it for induction. Then when you come to the IC U, you, you connect your systemic cooling. OK. So this is what we did in the Princess trial. We talked a little bit about that. We had uh the intervention was pre hospital cooling. We started inter arrests, very challenging concept. We started during CPR uh and then the the control group was cooling started IC U. So it was very, very early cooling compared to late cooling, I would say so early versus late in this trial and and pretty much the same patients by standard witnessed the cardiac arrest and all rhythms were included in this trial. And we have uh we had a predefined subgroup, the patients with ventricular fibrillation we discussed so long before the trial if you should only look at this group. But we at that time, 2010, the guidelines were, you know, cool everyone. So we this this subpopulation is about the same as the Haka tribe, 275 patients. So how did we succeed with the with the intervention? Well, we had the aim to start cool the patient at 15 minutes but we didn't really get there. But the median time to cooling is 19 minutes. That's pretty early if you compare to some of the other trials after two or three hours. So that's when we started. And we could see we had the C PC one and two as the primary outcome, a neurologic outcome at 90 days. We could see when you looked at the whole group, we couldn't see any significant differences. There was some 3% difference, but it wasn't statistically significant. But then if we look at the, at the ventricular fibrillation group, we could see a clear signal here, it wasn't statistically significant, but it was a clear signal, almost 9% absolute difference in this group. Um So this is an important finding and we looked um also complete recovery C PC one where you can go back to what you did prior to the cardiac arrest. And here we had a little bit of a stronger signal in the, in the whole group. But espe especially in the, in the ventricular fibrillation group because here we had significant differences, almost 30% absolute numbers. So this is a very strong signal. So we could conclude that if there is a uh effect here in our, in our, in our population, it's in this group with ventricular fibrillation. And we looked further because we had done a previous study, 200 patient safety and feasibility study published before um the Princess. This is Prince trial. So in total, we had randomized about 860 patients with the same study criteria. And this is not a me analysis. This is individual patient data we pulled uh by the first rhythm in these patients. We could see this is C PC one and two. In 90 days. This published a couple of years ago in critical care uh that we have significant differences in, in, in, in the group with, with shock of the rhythms. But when you move over to the non shocks, we couldn't see anything. So if and this is not enough to, to change guidelines, it's a subgroup and it's to, to study pool. So we have to move on with the, with the, with the second trial, but we will not include these patients because we see nothing here and it will just dilute our study. So going on to Princess Two, what we are about to start in January next year, our hypothesis is that ultrafast hypothermia and cardiac arrest with shock rhythms, increase survival with complete recovery compared to normothermia. So that's our starting point and it's a multi center, basically European or city. We're looking for some us sites too. But now it's a European moment we will look at in inter rest and also very early post ros cooling imme fibrillation. And this is a big, big study, of course, many different countries a re involved already. Uh uh We look at it's, it's similar to the population that we had in Princess. We have two different things. The shock the rhythms. And also we have the post ross. So you can include the patients from the first arrival at the scene, from the ambulance, you have 20 minutes window to, to include the patients. Um So and also this is the sa me picture as I showed uh some time ago. And the difference here is that the control group will use normothermia and not late hypothermia. So that's the difference between the 22 trials I would say. So we're doing the intervention AC LS and very early cooling, you continue to cool during the transport to hospital. And at the IC U, you apply systemic cooling for, for 24 hours and then you have the fever control just for three days and then you have a standardized blinded prognostication and you have a blinded assessment of outcome after 90 days. And in the control group, you do the same thing but without any hypothermia. Uh and we have the primary outcome measure is, is a little bit different from most because we think that Mr S3 is not a good outcome. So we have narrowed it down to be more a complete outcome but the patients can be independent. So Mrs 0 to 1 and the main secondary outcomes you see here uh survival uh and, and, and the regular ones. So what's the timeline for this? Yes, we will start in a couple of countries uh at maybe 78 sites during the first quarter. And hopefully we are enrolling with, with a full inclusion rate uh at the end of next year. And if you're interested um to know more about the study or even participate in the study, please, you can go into our website or you can contact me with the email. If you're interested to participate, we will have some sites here in Italy at least three or four. So that's really great and, and uh we have room for more in our family. So just to conclude, I think this is maybe just a conclusion from yesterday. So we have new guidelines and a lot of new knowledge. But the clinical practice diverging a lot, we do differently, different things. So there's definitely room for more studies. I think that's what we can say everyone in this room and we will have some new studies ongoing and they're about just about to start that will help us, you know, to, to, to really um uh get a better grip of what we should do clinically because that, that's, that's, that's we wanna do. And then um the synopsis I got last night was this trial? Early 33 is an upcoming trial in Vienna based Professor Beringer. And uh they will compare um hypothermia to 33 compare for 48 hours versus normal theia. And we will probably hear more about that uh later. But that's also so four very interesting tribes um for you guys to, to keep track of. Thank you so much. Created by
