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Hello, my name is Dominic Summers. I'm one of the consultant transplant surgeons from Cambridge. Thank you for asking me to talk uh in this forum. I'm sorry, I missed some of you live the other day. I got caught up doing something else, but this is the same talk. Now, this is a talk about a research project that I'm involved in at the moment. Um And I thought it might be of interest um to this audience because I think I've found through my career that trying to be an academic surgeon is very challenging. I think compared to other clinical academic specialties because you have to spend the time operating in order to be capable of continuing to operate to a high enough standard. And that really limits how much time you can spend doing clinical research or uh or bleeding basic science research. And so throughout my academic career, I've always tried to do things that really can only be done by surgeons often in collaboration with, with scientists. Um because I think as an academic surgeon, you have to recognize your limitations, but also the things that you can bring that nobody else can. And hopefully, this is an example of a research project that that surgeons can bring. Um that is only possible because I have this sort of Juul. Well, so hopefully, this gives you an idea of how you might be able to do. So, the subject today is about a feasibility study. A this is a pilot bit of pilot work that we're doing at the moment in Cambridge were just about to start about something called uncontrolled organ donation. Uh And the pilot is about to start in the next, in the next few weeks. So you may see it around. Hopefully not on the news. Um Just a bit of a background to what's been going on. You've heard all the uh all the terrible things that are going on in the health service over the last decade. But in transplantation, it's really bucked that trend and there's been a 24% fall in waiting lists, a 57% increase in the number of transplantable organs and a 75% increase in the number of deceased organ donors. So this is a really rare good news story. Where have these donors come from? Well, it hasn't come from living donors, living donors, you can give one kidney whilst just alive and they pretty much remained constant, but there has been a marked increase in both number of donation after brain dead donors. So DBED donors, which are the traditional donor type, they've gone up by about 50%. Um but the real increase, these proportional increase has come up in the increase in D C D donation after circulatory death donors. Um The other thing that has changed has been the increasing age of donors. So back in 2009, just over a quarter of patient's were um were under the age of um uh over the age of 60. Whereas by 2018 2019, it was almost 40%. And actually, if you look at kidney donors alone, almost half of donors are over the age of 60. Now, what are the implications of those things? Well, this is what's a risk model, a hazard ratio forest plot of what's called death censored graph survivals. This is how well the kidneys survive, excluding whether or not the patient is still alive, you take them out of the equation if the patient dies. So at this death sense of graft survival, you can see this blob in the bottom left hand corner, 18 to 30. So that's the baseline group of the donors age between 18 and 30 as a donor age increases. So the donor range between 30 and 31 sorry, 31 50 you have a 1.7 times chance of the graft being lost, these error bars of confidence intervals and as the donor gets older, so the outcomes get much worse. So you're three times as likely to lose your kidney within the decade if the donor is over 60. All the other factors in the model essentially don't worry about them. They don't really matter that much donor ages by far and away, the most important variable. And the other thing is just if we look at the pink blobs where it says type, it talks about the donor type and there really is no difference between DCD and DBED donation after circulatory death and donation after brain death. So just to summarize where we are so far in terms of donors, the changes in infrastructure, in terms of specialist nurses in organ donation, asking everyone who has treated withdrawal in it. Do the national organ retrieval service know rose. This is a professional organ in travel service that started in about 2010. And the way organs are offered have all facilitated major increase in donor numbers over the last decade. But really the big change has been because partly because we've identified a new source of donors, which is DCB donors, but also using kidneys from more marginal donors. So donors who are older kidneys from DCD donors work as well as those from DVD donors. And so it can be used without penalty. But kidneys from elderly donors carry substantially more risk to the recipient than kidneys from younger donors. So we can increase donor numbers, but we pay a penalty for it. So if we could identify a new source of young donors, this would be ideal. Now, of course, there's the other side of this, we talked about how it is for recipients. But if we think about organ donation as a whole, organ donation has overwhelming public support. And we know that when the law changed the other year to have an opt out system, um 85% of the public said they supported organ donation. It's a core part of bereavement care if any treatment is withdrawn in I cou um your families are supposed to be asked about organ donation, but only a tiny fraction of the 300,000 people who die each year under the age of 18, actually become organ donors. If you remember back to my first slide, there are only 1.5 1000 deceased organ donors in the UK every year. So the big question is, where have all these other people gone? 85% of people once donate, there are 300,000 people possible, but only 1.5 1000 less than half a percent become donors. Basically, it's because of logistics. You don't dive the right thing at the right time in the right place. There is no way you can be a little container in the UK. This is a quote I'm received and I've been working with the air ambulance service about this pro proposal and this is from a family member and they said, I'm not sure if this is of help, but I lost my husband after response to my home and transferred to hospital where he died a short time afterwards. Sadly, I assume that because sometimes it past Jack was unable to be of help as an organ donor. It was obviously an awful time. And not only did I have to deal with difficult conversations with the coroner over two days, but Jack was unable to fulfill his last wish and others couldn't benefit from organ donation. So, is it possible to get those from the, from this group of people? The uncontrolled toques? Well, some more numbers for you, 30,000 out of hospital cardiac arrests every year of whom only 8% survived to discharge in the UK. And that's a pretty typical figure internationally. In Spain, there were 500 U D C D, uncontrolled DCD donor kidneys are transplanted in the last five years. How did they do? Well, the top line here where it says S CD, that's a standard criteria donor. And that means a donut under the age of 60. And the results there are fantastic as they are in the UK, a 10 year graft survival of about 80%. The bottom line, the E CDS of the expanded criteria donors and these are donors over the age of 60. So much as they are in the UK, they do much, much worse compared to the scds. But of course, the line were really interesting is the U D C D, the uncontrolled donors. And you can see the trajectory of the gradient is the same as the sec. These, these a young fit donors, the risk is all at the start. There's a risk of primary non function where the kidneys just don't work at all. You put in the kidney and it doesn't work. And the risk of that is much higher for you DCD kidney compared to an sed kidney. So the rate of primary non function in an E C D. So an elderly kidney in the UK is about 4%. And these make up half of all the transplants we currently do. So these are risks that we are currently taking the risk of primary on function in France and Spain is somewhere between five and 8%. It's a roughly doubling of the risk of primary non function. But you can see that the lines cross at about a year and the long term survival providing they get over this initial problem with primary on function is much better than for expanded criteria. Don't how many transplants are? They're well, it's difficult to estimate this, but it's, it's almost certainly at least an increase of 25% based on the Spanish data and some other data from Copenhagen. But it's very challenging to do this. So it may be as low as 5%. On the other hand, we may be able to solve some of these problems, particularly this problem with primary on function is that keeping dead or alive with some new technology and I'll talk about that a little bit. But if we can, then potentially we could increase 10 numbers by as much as 100%. So as part of the proposal, the European Society of Transplantation paid for me to go out to San Pander. And if you're looking for travel grants, highly recommend having a look at their website. There's a lot of small grants for travel, for fellowships and things. They paid for me to go and visit doctor my Nombres in North Spain. You know Santander from the Bank, of course, but this is it. Um and it's a city on the north coast of Spain. Most people live whether red blobs are concentrated around the city itself, the rest of it's mountainous, it's very nice place to live. Uh Now, why did I go there? Well, because it's slightly smaller than Cambridge, it has slightly fewer hospital beds. The donation rate in the UK is 24 per million of population. Spain has the highest donation rate anywhere in the world but Cantabria where some hand areas has an even higher donation, 86 days per million population. And if we had anywhere like this, we could fix our problem with the shortage of donor organs. We have an opt out law saying that family, that individuals have to opt out from organ donation, otherwise they will be assumed to have consented to become an organ donor. Um The similar law in Spain, the law is slightly different. So you are allowed to do different things, two potential donors. So for example, in Spain, you are allowed to place large groin lines and heparinized patient's in order to facilitate organ donation before the donor has died. Whereas in the UK, that is completely against the law, we have to be completely certain they are totally dead before we even touch them from a donation perspective. So there are some differences which means that we can't just lift their protocol. And Plunkett Straight in Cambridge. So what are we looking at? This is the protocol from Santander that we are copying. So we're looking for patient's without a hospital, cardiac arrest age between 18 and 16, 60 years have a witnessed cardiac arrest at the start of advanced CPR intubation professional CPR within less than 15 minutes and in East anglia, that's a record that is, that is almost always achieved. Um exclusion criteria. We can't cope with trauma. You'll see that the circuit we use to preserve the organs requires a lot of anti coagulation and we have no way of managing bleeding, intrathoracic bleeding as part of the donation process, we have to transplant the organs. So these would be standard exclusions. So how does it work? Well, it starts with the cardiac arrest and calling for an ambulance at which point they start what's called a Lucas device performing automated CPR. You might see these in A and E there's an early telephone call to uh the donor team in Cambridge. In this case, it will be me. Um And then some more data will come through so we can look them up on the organ donor register before they arrive in hospital. We also have to speak to the coroner to make sure that we have the coroner's consent for this process. So these are some photographs from uh from Spain. They do involve clinical pictures. So just be a bit warned, this is the donor team. This is five o'clock in the morning and this is their intensive care unit. This team is made up of cardiovascular surgeons. They're not actually related to transplantation at all, but they happen to be the people who can cannulate the groin in the in Addenbrooke's. This will be performed by the transplant consultants. So this is their I cou so fairly typical. I cou the patient comes in in the back of an ambulance accompanied by a member of the family, which is very typical, has to be a witnessed cardiac arrest. So there's usually someone with you, the resuscitation happens on route. They arrive in I T U and they are continue to be resuscitated. So the donor has a pulse on arrival. The donor team is still just next door. Um and the I T U team is continuing to resuscitate as they would for any other patient in this in this situation. Ultimately, they confirmed death. They gave some heparin and put the Lucas, this this resuscitation device back on and then they're prepared to cannulate the groin. Now, in the UK, we're not allowed to re perfuse the brain after the declaration of death. So we can't put the Lucas back on. We just have to get on with this cannulation very quickly. But other than that, the process is the same. We are, we are because of the law differences were quite experienced with, with rapid cannulation. So, the idea is to try and preserve the organs in sight you in the abdomen without perfusing the brain. If you perfuse the brain, they're not dead. Um And clearly, that puts us in a very difficult, both legal and ethical position. So how can you preserve the organs will be placed lines via the groin, femoral cannula up the, up into the IV, see an arterial cannula up the femoral artery and then an occlusion, what's called an ender clamp occlusion balloon in the descending thoracic aorta. And the idea is that this circuit, it's called a normal thermic regional perfusion circuit pumps oxygenated blood around the abdominal organs and preserves them. So this is the venous cannula going into the femoral vein. That's the femoral artery cannula with the side port for the balloon. This is the balloon going up and this has to sit below the sub Kleynhans and above the renal vein above the renal vessels. And this is the circuit essentially normal thermic regional profusion is basically an air command machine with the difference that rather than trying to re perfuse the brain, keep the brain alive. This is just trying to preserve the abdominal organs for the purposes of organ donation. And we use NRP regularly all the time for our standard controlled DCD donors. So about half of the donors we normally do will use this process. Um and you can see the oxygenated blood is going up through the red tube and then the, the uh the blue tube is the deoxygenated blood before it goes around the oxygenator and it's pumped around again, they take an X ray to make sure the balloon is in the right place. Now, how do you manage the families? Um There's lots of evidence that in the circumstance of bereavement organ donation is a very good thing for families. Many of my specialist nurse colleagues who take a lot of the consent. They say it's very difficult to make someone's day worse by asking them about organ donation. On the day. They've witnessed their loved one collapse and die in front of the. Um And there's quite a lot of evidence that, that it's often seen as the one good thing that comes out of terrible tragedies is that organ donation was a possibility. So, in general, both the experience from other types of days in the UK and also from the experience in France and Spain families are broadly pretty supportive of this, but clearly, it's a difficult and sensitive time. So what how we're planning on managing the families, which is again, it's slightly different to Spain. Is that at the moment of withdrawal of treatment in the in the emergency department that will be in the UK at that moment where all the team are asked when they have any ideas, whether they're in agreement to withdraw treatment, the family members who are usually witnessing this event will also be asked whether we can keep the option of organ donation available through another small procedure, which will be to place them on the machine and then we'll place them on the machine and then then the family can come back in and this is what they see. They look very much like any other dead body in the emergency department. So the hands are out and cold, the faces cold, but they are covered in a sheet and they are connected to the NRP circuit. Yeah. So and then you approach the family as part of a standard process of organ donation consent. You go through the formal process later, this will buy you about four hours in which all of the other systems can take place. So then the patient was taken to theater and this was the team in Spain and you'll have to take my word for me for it. This was a beautiful looking kidney that was transplanted and it worked very well and had a primary function. So the timing limits for this. For this proposal, a sister liter, the start of CPR has to be less than 15 minutes. The start of the normal thermic regional fusion has to be done within two hours. And we need to start, we need to get to the theater to take the kidneys out within about four hours. And the aim of these time limits is to try to minimize the risk of um of primary non function. We can't, we can't have vagueness about this because the risk of irreversible ischemic damage to the kidneys is so high. So those of, you know, Adam Brookes, the plan is that they will come into the emergency department, they'll go up to theater 12 whilst there on the circuit essentially to clear them out of, out of a any and to get families into someone a bit more comfortable and the families can also have access to the ICU relatives room. So, what are we proposing? Well, this is a multi work stream feasibility study, work stream. One is, can we do it at all delivery of the pathway? What we aim to do? Well, we'd like to get five, what are called utilized donors. These are donors in which we take an organ and transplant, at least one of them. Um We will be looking to see how well the kidneys do, whether we get prime in on function and how, what the function is like is that realistic? Well, over the two year period, pre COVID there, on average, just under 25 donors per year, within a 40 minute drive time of Cambridge, which seems to fit with our timings, which is the orange circle. These are conservative estimates if you want to increase under, if you increase donor age to 65 years, then double the number of potential donors there. As many people who died between 60 and 65 as they were under, under the age of 60. And similarly, if you remove the need for a witness cardiac arrest, um and the start of CPR in less than 15 minutes, you can increase it by, by a factor of tens there around 250 potential donors. If you remove that. Now, that's because most people when they witness a cardiac arrest, what the first thing they do is usually not look at their watch. So unless there was a 999 called the second it happened. Most people are pretty vague about when it started. Uh and we have to exclude them because we can't risk primary on function. But if we had a way of solving that is the kidney dead or alive, then we could, we could eliminate that and increase the, expand the pool. You know, enormously, we are going to be assessing family experience that there's going to be qualitative research, semi structured interviews with bereaved families. Three months after the death of their of their relative. Um we will be doing, we'll be assessing the resuscitation pathway to make sure that the resuscitation is as good for this team as it is as this group of patient's as it is for everyone else. The experience from France and Spain is that actually dramatically improved resuscitation with this pathway because you have to be so hot on the timing as you need so many extra people and you end up with a helicopter and all the kit. So we expect that this to show that resuscitation gets better. And ideally, we will have a survivor because we've improved resuscitation. Um but it's useful to be able to show this as you prospectively. And the final part of this is an organ assessment, the basic science part of this. So can we answer the question of, is this kidney dead or alive and reduce the risk of primary malfunction and expand the donor pool? We're not going to be able to answer this um definitively, but this is the pilot part of it. The first thing we're planning on doing is some RNA transcript tonic work. So the uh the first thing that sells do in the process of uh of signaling is produce R N A. If you work further down the line and wait for proteomics, then this is much further down the pathway in it, we anticipate that has a sort of scream for help as the kidneys are on the verge of irreversible damage. Many of them may never actually process the proteins. So we hoping that the earlier signal that the kidney is irreversible damage will be in the RNA transcript own. So we will be measuring this and we're only going to be doing this on very small numbers. So we won't have a definitive answer. But hopefully it'll show that we can take these samples and it will give us some way of powering the future study if we're successful. The other thing we do is we use a lot of ex vivo norma thermic perfusion. So you take the organ out and put it on a rig that pumps blood around the, in this case, this is a liver, but there's a kidney machine as well and it gives you lots of numbers out of it. We don't yet know what those numbers mean. But the anticipation is that this will help us decide whether kidneys are alive or dead. Now, one thing we've done a lot of is patient and public engagement. I think there's a lot of skepticism about research and patient, of public engagement. But this has been absolutely fundamental to this whole process. We've really been driven into doing this work by the families of bereaved young people who have said, why can't you provide organ donation for these people? Whenever I run into a problem with a regulator, an ethics person, I have been able to bring one of my family members along to berate them and say, you know, this is a service that we want. We really wish our loved one could, could have been a donor and that's incredibly effective. They've also helped design the consent forms. The approach is uh we really couldn't have done this without very strong public engagement. It's a big team of people, some of these names you may know. Um So just to sort of round up, I think that not having a UDC program denies the opportunity for organ donation for many people and families. And I think that's the major reason for doing this, that we are failing in providing a good bereavement care by not providing organ donation for this. For this group of patient's, you D C D currently provides a large number of high quality kidneys for transplantation in France and Spain. And combined with the novel technology that we're hoping to develop this has the capacity to substantially increase transport numbers in the UK would potentially be as transformative as controlled DCD donation has been in the last decade. From a medical student perspective. I think the transplant research is full of complex, scientific, ethical and legal questions. This has been an absolutely fascinating career. It has pre flexible working because we can't predict when the transplant sort of donors going to happen. So I have quite whilst I am occasionally, that's for the middle of the night, the rest of the time, my work is pretty flexible and I think that makes it fantastic as an academic specialty. There are very few surgical specialties that enable you to do as much in the way of research. And I think that reflects, that's reflected in how much research my colleagues do. And finally, um I hope this has given you a taste for the benefits of transplantation. One of the major challenges we have is that people don't let their families know and they, you can sign up, you can join them doing the register and make sure that your families know what your wishes are. So should the worst happen? You can make sure your wishes are fulfilled. Thank you for listening. If you have any questions, I'm very happy to take questions by email. Um If anyone wants to make contact with me or the team, we do often have research projects for students. If you want to do some programs or want to come along for, for higher research. Once you're qualified, uh you'd be very welcome.
