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Maybe a couple of minutes for everyone to get uh to get in and then we'll, we'll do the introductions, pain. I, OK. Give it one more minute and then we'll stop. Right. OK. We'll do introductions and then we'll let everyone else join as they can. So welcome everyone. Thanks for joining us today. I want to welcome you to the next part of our series. For those who don't know, it's our new initiative in collaboration with over 10 universities across the UK designed to enhance anesthetic education and address gaps not always covered in medical school. Just wanted to signpost you to our medal page to keep updated with all our future events and not to forget to um complete the feedback form at the end to receive a certificate. So now I'd like to hand over to Chris to introduce himself and the speaker for today's session. Thanks. Yeah. Um My name is Chris Ha. I'm 1/4 year medical student at the University of Edinburgh. Uh and I'm also the Secretary for Our Anesthetics and Critical Care Society. Uh I'm very happy to introduce Professor Tim Walsh, who is the lead for the Edinburgh Critical care research group um and also does a bit of teaching for us uh as part of our anesthetics indicated degree. Um And he's gonna be talking, talking to us today a bit about blood transfusions. Uh Yeah, take it away. Ok. Thanks Chris, thanks for inviting me. Um I'll just uh get my screen shared and hope that that all works. Ok. So uh can I just check that's all working for you? I think it probably is based on our rehearsal. So I will kick off and please somebody shout if anything goes wrong with the er slide transfer or you can't hear me. So, um th this was advertised as blood transfusion and fluids, which is actually a vast subject. So I thought about it a little bit and I thought I would just talk about blood transfusion. Um and one of the reasons I wanted to do that was it's universally important in medicine, um and particularly important in anesthesia and critical care. Uh But it's also um something that for which the evidence base has changed enormously in the last 10 to 20 years. And which sometimes uh I think medical students and junior doctors are a bit puzzled by what we do. And so what I wanna do, it's an area I've been involved with um research wise for about the last quarter of a century almost. Um And one of my main research interests and I'm gonna tell you a bit of a story around some of the key aspects that's changed our practice and then rehearsed for you. What we think current best practice is in terms of what you'll see happening and what uh you should be doing when you are er, doctors um accepting that the evidence base may evolve a bit more. So I've called it blood transfusion elixir of life question mark because um there's always this assumption that receiving blood transfusions must be good for you. And what we've learned is that that's not necessarily the case. So one of the key concepts to understand is that for most transfusions that you give the transfusion is a treatment to correct a complication, anemia or hemorrhage caused by a disease. And that disease could be enormously diverse. So it is not a disease or a condition. It is a treatment to correct a complication of a disease. And the first thing I'm gonna say is that most of this lecture. In fact, virtually, all of this lecture is not about this situation. This is a picture taken when I was first a consultant, uh anesthetist, I was a liver transplant anesthetist. And this is a picture taken at the end of a liver transplant that didn't go particularly well. And those are the products that were delivered. But I put this slide up to highlight that I'm not really talking, I'm not talking about the patient who is bleeding to death, who has severe hemorrhage where blood transfusion is life saving. There is a literature there mainly from emergency medicine and the military and so on which does suggest that you should use blood and fluids fairly conservatively in the field or at least until you have achieved control of the hemorrhage. However, you do that. Um But I'm not talking about the patient who is bleeding to death where giving blood is life saving. What I'm talking about is the patient who has a low hemoglobin has anemia, may be bleeding a little bit or has bled or just is anemic. And we're not sure what hemoglobin is. OK for that individual. And whether we should give one unit of blood, two units of blood, et cetera. So the next thing I wanna highlight is what a hemoglobin means. So we virtually always transfuse in response to a hemoglobin concentration unless the patient is bleeding to death in front of us. And a hemoglobin concentration is essentially the relationship between the red cells in the plas in, in the circulation and the plasma volume. So that's the one in the middle. So a healthy euvolemic person has a red cell volume of about 2 L, a plasma volume of about 3 L and a blood volume of 5 L. And that's what generates a hemoglobin in the normal range. Now, in hemorrhagic shock before you've given any fluids of any type back, you could still have that hemoglobin because you've lost whole blood. And it's important to remember that, but almost as important over on the right is that you only need to expand the plasma volume with clear fluids, whether they be crystalloids or colloids or whatever they are by around about 1 to 2 L to drop the hemoglobin to less than 10 g per deciliter or 100 g per liter with your red cell volume being the same as normal. So you always have to remember that a hemoglobin is a concentration, not a red cell mass. And what we're really interested in is what red cell mass is available to deliver oxygen around the body. The next thing I just want to introduce is is is grades of anemia. So the in fact, these this slide is slightly out of date because the WH O has slightly changed their definitions, but it doesn't really matter. But you can see on this, that they, the the definitions of of moderate to severe anemia are less than around about 95 94 95 g per liter or 9.49 0.5 g per deciliter. And yet what I'm gonna talk a lot about in this talk is tolerating moderate to severe anemia in patients who are really quite sick. And often people think how can that make sense. But that is what the evidence is telling us for many groups of patients as I'll explain. And I also wanna think about what causes anemia during acute illness. And that could be a patient in the ICU. It could be a patient with severe illness on a medical ward and it could also be a patient undergoing um who, who's, who's has undergone or is undergoing major surgery. So the patient could have preexisting anemia before the illness or the surgery starts. And that's obviously very important or they could have acquired anemia. And as I showed you with that slide about hemoglobin concentration, a lot of that could be due to hemodilution with clear fluids when the red cell mass may be only slightly reduced or perhaps even normal. Now, obviously, you may lose blood from blood sampling or from actual bleeding from various sources. It may be that the red cells in your circulation, which if you remember from your physiology last typically about 100 and 20 days, something has main meant that they survive less in the circulation and they're being removed more actively. But importantly, it may be that something has switched off your bone marrow production of red cells, particularly when this is occurring over days or several weeks. And this is the case in the perioperative period if that's prolonged and especially in critical care where people may be sick for some time before an illness, be in ICU potentially for days to weeks. And then so and then recovering for some time and red reduced red cell production could be due to abnormal iron metabolism. Cos we need iron for hemoglobin. It could be due to other nutritional deficiencies, especially B12 and folate. And it could also be that the normal body's response to drive the marrow. The secretion of erythropoietin by the kidneys is abnormal as well. So it could be that the red cell production is abnormal for various reasons. Now, if you take a patient who's in the ICU or has recently been in the ICU and who is anemic and you measure the things you can send off to biochemistry. This is typically what you'll see. And without going through these line by line, which we don't need to do. The key features that these illustrate is that these patients have abnormal iron metabolism. And what happens is that iron is sequestered away from the circulation into the liver and the reticulo endothelial system into storage iron unless iron is made available for red cell production. In addition, even if your hemoglobin is down at nine or 10. Whereas if you've just been to the blood bank and given some blood as a blood donation as a healthy person, your epo levels would shoot up to drive your marrow to replace that. Your erythropoietin levels are normal or only slightly elevated. They're inappropriately low. And you don't demonstrate reticulocytes in your blood, which shows that the marrow is producing new red cells. So something is going on here. That means the red cells are that the marrow story is not responding normally. And and these are nice sort of cartoons taken from um a, a really good article published really probably more than 10 years ago now about the anemia of chronic disease. And the fact is that patients with acute inflammation, which is what virtually all um ICU patients have and many perioperative patients have after major surgery, they have an acute anemia of chronic disease. In other words, the features that occur are the same as in someone with chronic disease, like rheumatoid arthritis, cancer and chronic inflammatory diseases. And what you see is that you get some sort of inflammatory hit from whatever has gone on a surgical trauma, major surgery, sepsis, whatever it is. And those inflammatory mediators, especially interleukin six, switch off your erythropoietin production in the kidneys. So you don't get that normal drive in the bone marrow occurring. And that means that your bone marrow doesn't start to generate red cells normally, which is one of the reasons you don't see reticular sides. The other thing that happens is interleukin six, especially causes the release of a substance called hepcidin, which you may or may not have heard of, which is the key regular age of iron metabolism. And what Hepcidin does in the liver is it starts driving available iron into the reticulo endothelial system and macrophages and reducing its availability. And the other thing it does is it blocks the gut from absorbing iron. So that even if you are feeding people or giving people enteral iron, it wouldn't be absorbed because hepcidin blocks it from being absorbed. So you see these features of ferritin going up which stores iron down regulation of transferrin, which is what normally is transporting iron around in the plasma and up regulation of hepcidin, which basically reduces iron availability and iron absorption. And these these macrophages in the reticuloendothelial system, they alter their iron handling and what that generates is what is sometimes called a functional iron deficiency. The body has normal total iron stores, but they're not available to generate red cells. And overall that means that your bone marrow doesn't respond by generating red cells. So people who have an inflammatory illness, whether it be chronic like rheumatoid arthritis or acute like severe sepsis in the ICU or pancreatitis, something like that. Their bone marrow is not responding normally and this is a major contributor to anemia in sick people, particularly when they've been sick for some days. So the next thing to think about is what red cells for or red cells are obviously there to deliver oxygen around the body. Now, normally, the oxygen delivery around the body is the cardiac output multiplied by the arterial oxygen content and more than 99% of oxygen in the blood is bound to hemoglobin. There's a very small amount soluble. So the oxygen content of blood is very reliant on the hemoglobin concentration. Now, in health, we have a cardiac output of around 5 L per minute. An average size adult and we have about 200 mils um per 100 mils of oxygen carried in our blood, which means that we deliver about a liter of oxygen around our body from the heart and lungs every minute. But our body only uses at rest about 250 mils. So we have a oxygen extraction ratio of about 25%. So we have a big safety margin in the body for increased option requirements. And the balance between these two things is what often becomes awry in severe illness or in shock. Um and that is where potentially the delivery of oxygen to tissues may be inadequate and hemoglobin concentration may be important. And this was one of the reasons why historically, it was always thought that if you're sick or a surgical patient, you need to try and maintain near normal hemoglobin concentrations, I'll come back to that in a moment. So blood transfusions, what a what actually happens when we give blood. So probably many of you and go and give blood. So, post donation, we look to deplete those red cells that's standard. Now you remove the plasma and the platelets and they go off to be to generate F FP and platelets and then you store those red cells in a storage medium which is designed to prolong the red cell life. And in the UK, we can store blood for up to 35 days. It's 42 days in many countries, it's 35 days in the UK. Interestingly, the, the, the, the length of time you're allowed to store blood in the blood bank is determined by the number of red cells that survive if you re infuse that bag of blood or a sample of it back into a healthy person. And it has to be greater than 75% of the red cells. That's the way we judge it. It's nothing to do with whether the red cells work. It's just whether they survive. And that's, that's relevant to some of the things I'm gonna uh talk about with, with age of red cells. Now, you may think, well, that's fine. And at the top left, there is a lovely normal red cell. Remember that Ellipta shape that can deform to go through capillaries because it's actually bigger than a capillary. And it needs to be flexible. And what I've shown going from top left down to bottom, right is what happens to red cells during those 35 to 42 days. And I'm not gonna go through all that text, but lots of stuff happens to the red cells that means that they theoretically and in the laboratory can be shown that they don't work. Normally, they don't deform so that they're, they're more difficult to get through capillaries, they change shape, um their membranes ch change and the amount of D PG in them changes. And there are lots of reasons that they may not transport and release, release oxygen in the capillaries uh when they're transfused. And so there's always been an interest as to whether all the blood, even though it's allowed to be given works well enough. And I'm gonna come back to that a little bit later. So it follows from that, that whereas often we, we think that we're giving a blood transfusion is always good. We know there are complications of blood transfusions and this is a table taken from a recent international guidelines which I'm gonna come back to about other issues from just a couple of years ago, just showing the current estimates of the major reactions that can occur to blood. And of course, there are others. But I highlight here that if you look at the bottom, the risk of getting a virus from a blood transfusion is still there, but it's pretty small, it's less than one in a million. But if you particularly look at things like transfusion associated circulatory overload, that's taco, then the risk is close to one in 100 and that's a serious complication. So where does all that blood go that we that, that we donate? So in the U in the UK, around 2.5 million units of red blood cells are transfused per year to around half a million patients. And the risk of transfusion related death is around about 5 to 6 per million blood components issue. So it's rare, but obviously, it's a disaster when it happens where it's iatrogenic due to a blood transfusion, the risk of transfusion related major morbidities. So, not death. But these other things like taco and tr transfusion associated lung injury is much higher. It's about 65 per million blood components used. And I've just highlighted at the bottom that the most common cause of death now associated with giving a transfusion is transfusion, associated circulatory overload. TCO giving blood and putting a patient into heart failure. So historically, until about 20 years ago, the year 2000 or a quarter of a century ago, there was a general belief that blood is good and correction of anemia is good. And there was a thing which you probably won't have heard of but was around when I was uh a training doctor of a 1030 rule that you should aim to have a hemoglobin above 10 g per deciliter and or hematocrit greater than 30%. And they're more or less the same thing and many surgical or critically ill patients as a results received blood transfusions. There were huge numbers of blood transfusions given to surgical patients undergoing major surgery and in the ICU. So what challenged all of that? So this is a very famous study, probably one of the most most famous studies in medicine, almost, but certainly the most famous study in transfusion medicine. And it's called the trick study. It was a Canadian study. It was done in the late 19 nineties and it was done in Canada. And they asked a very controversial question. They said that in ICU patients so sick patients in the ICU, most of whom were on a ventilator if you compared, if those, those patients become anemic. And remember that's very common in the ICU because of all the reasons II spoke to you about the causes of anemia in particularly bone marrow, switching off and bleeding. And that sort of thing, if the hemoglobin drops below 100 g per liter or 10 g per deciliter, you'll ran, they randomize the patients to either get blood to keep them above that level. And that was very much standard care at that time, the 1030 rule or just let that hemoglobin drift down and down and down and only transfuse them if it dropped below 70 g per liter, 7 g per deciliter, which as I showed you is moderate to severe anemia. This was very controversial at the time. Now, that study was supposed to have about 1400 patients in, but it was stopped after about 840 patients cos it ran out of steam and they published the results they got at that time. That was the one of the biggest ICU studies ever done at that time. We now do much bigger trials which shows how, how, how we've moved on. But that was a big study at the time and over on the left, you can see the mortality of patients and you can see that the lines separated and the restrictive group who didn't get so much blood seemed to have a, a better survival. It didn't reach statistical significance, but it was an underpowered study. And the separation is very clear. And over on the right hand side, you see the separation of hemoglobins that resulted. So they generate an important difference and there was a trend towards better survival from not getting blood and being anemic. And they had two predefined subgroups. One was patients with an Apache score less than or equal to 20. Now, if you're familiar with Apache two score, it's an in illness severity score from the 1st 24 hours in the ICU that predicts your hospital mortality and a patchy of 20 is about the average for ventilated patients in the ICU. It's about half or above and half or below. So in the, in the roughly 50% of people in the I patients in the ICU in the least half severe in terms of their mortality risk, it was even more beneficial not to get blood and to be left anemic. And that was actually statistically significant. And at the bottom, in younger patients who probably have more car cardiovascular resilience and reserve, it was also statistically significant and it was better to not get blood. So when you look at the trick trial, the overall mortality at 60 days, which was the primary outcome was a 25% which is pretty typical for IU at that time, but a bit better than that. Now, it's now probably around about 20%. Now, the difference in mortality ranged from 3 to 8% overall depending on the subgroup. With these bigger differences being in younger, less severely unwell patients favoring not getting blood. And these patients got a difference of a almost three units of blood and 33% difference in getting blood. All the liberal group got blood, only about two thirds of the restrictive group got blood at all. So this really changed things. But even more interestingly, if you think that the reason we give blood is cos we believe we're increasing oxygen delivery. And that at the time was thought to be the main thing that caused organ failure in critical illness. And so the assumption would be is if you had a higher hemoglobin, you would get less organ failure and that would translate into a lower mortality. But in, in the out in the secondary outcome measure, which measured a thing called the multiple organ dysfunction score or mds, which is a way of adding up the organ failures that occur during an ICU admission. The actual score was lower in the restrictive group. So it really challenged that idea that having a higher hemoglobin was necessary to prevent organ failure because it was preventing hypoxemia through lack of oxygen. The signals were the other way So what were the possible explanations for the tricks trial? It could be that transfusion is harmful. And at that time, there was no pi depletion. So there were white cells in, in, in the red cell transfusions. And there was quite a lot of evidence that those might be harmful to people. And the other thing is that blood often was a bit older in terms of between about up to 3235 to 42 days, often blo blood was in the sort of day twenties or older. Uh And maybe because of those changes in stories that I showed you those pictures of, maybe those effects of storage were causing harm or a mixture of the two. The other possibility is that anemia is good for you when you're sick. Because if you have a low hemoglobin blood might flow through capillaries better, particularly if the blood cells, the red blood cell transfusions, you give us have stiff nondeformable red cells in them. And the other thing is that it might be that most organs do not have an oxygen supply dependency and that their failure is actually due to something else. And in fact that almost certainly is the case, there have been quite a lot of experiments now that have looked at the relationship between induced anemia by hemodilution and whether you drop off your oxygen consumption in the body as an index that there wasn't enough oxygen. In other words, you're getting ischemic metabolism and generic lactate and that sort of thing. And most of those experiments suggest that in healthy people, especially you get down to a hemoglobin of four or five before most organs run into trouble if you're healthy. And the other thing is that we now increasingly understand that organ failure is much less due to inadequate oxygen delivery. It's due to inflammation and of course, blood might be pro inflammatory because of all those changes that occur during storage. So what's happened since the trick trial? Well, it's had a massive impact on transfusion practice and tolerance of anemia. And that is why as those of you are doing clinical may have already seen that we tolerate anemia in the ICU and perioperatively to levels that you might think crikey that's very anemic, but that's what the evidence tells us. And I'll come back to how that evidence has, has, has evolved. And as a result, there's been major major reductions in the use of red cells for surgery and in critical care as we restrict the use of red cells and only transfuse at much more anemic levels. There's also been a massive expansion of blood conservations and what are called patient blood management programs. And that's partly because we want to conserve blood cos it's a precious resource and we don't have enough of it. But it's also because of concerns that transfusing stored blood or allogeneic blood, which is stored blood might be harmful So it'd be much better to avoid the need for it. So there's lots of ways we're doing that as standard in hospitals. Now, some of that before surgery is screening people for anemia before major surgery. And if they have anemia, treating that anemia appropriately before their operation, so they're iron deficient, give them iron, check their B12 and FOLATE, et cetera, et cetera. We increasingly use intraoperative red cell salvage where we salvage blood from the surgical field and reinfuse the cells into the body. So that's used as almost as routine for many major surgeries in cardiac, um liver transplantation, vascular major vascular surgery, orthopedics. It's standard in many areas. And the advantage of that is that the red cells you're retransfusion are the patient's own red cells. So they don't carry those risks and they're all so fresh, they haven't been stored. So they're almost certainly working. Normally. We've obviously got this tolerance of anemia and, and the use of restrictive transfusion practice, which I've talked about. And we also increasingly know there are ways that we can reduce bleeding. And it's not for today in my talk, but there's a massive literature now on the benefits of oxamic acid in reducing fibrinolysis and reducing bleeding during surgery and in trauma. And so that's become standard care. And the other thing we've done is a lot more randomized controlled trials and I'll talk a little bit about those. So I've gone back now to this most recent guideline from the American Association of Blood Banks. So there's lots of transfusion guidelines and they get updated by somebody every year or two and this is the most recent one, just um 18 months or so old. Now, you don't need to look at any detail on here. But this hopefully you all know this is a forest plot from a systematic review. So we've, they've listed, they've searched and found all the studies which are randomized trials of liberal versus restrictive blood transfusion practice. And they've assessed them for quality and they've extracted the relevant data and then they've put them together into a meta analysis to synthesize all the data. And in fact, the, the upper panel which you can't read doesn't really matter, is essentially um with, with um a transfusion trigger of seven. And the one below is with slightly more liberal transfusion trigger. So they really try to organize all these trials. And the first thing you can see is there's lots of trials there. So the trick trial was really the first trial and now there's quite a lot of trials and some of these are small, but some of them are really quite large trials. And in fact, there have been four large trials since that review in a, in 18 months ago, which I'm gonna talk about in a moment. But what you can see, uh I'm not sure if my cursor works, but this is the sort of overall effect here and here. I'm not sure if you can see that, but you'll be familiar hopefully with meta analysis. And that is essentially showing that when you put all these data together, you don't see any effect on mortality from restrictive compared to liberal. They seem to be pretty equivalent when you add everything in together. And that's very reassuring that our default position should be to be restrictive and use a transfusion trigger of 70 to 80 or close to 70 probably as a default in almost everyone. And they further summarized um from the literature, when you take all the studies put together what this means for patients and I'm not gonna go into it in detail. I'm very happy to share the slides and, and leave them for you to see if that's useful. But over on the right hand side, I've put that red rectangle in into a plain language summary of what they think. All the evidence means that transfusion threshold, light has little or no effect on mortality. In other words, being restrictive overall is OK. He has little overall effect on M I. We'll come back to that in a minute. Little effect on heart failure, little effect on the risk of strokes, on the effect of rebleeding on the effect of infection uh on the effect of thromboembolism. In other words, um um DVT and PE and so on, little effect on delirium where there's a lot of interest because delirium might be due to reduced oxygen delivery to the brain. And what it certainly does is it reduces the use of red cells and the exposure to blood enormously. So, the key thing is that the default position is we should be restrictive and that's what you see happening. And they made this recommendation, which is their main recommendation that for hospitalized adult patients who are hemodynamically stable again, reiterate. This is not about people who are bleeding to death or have major hemorrhage. The international panel recommends a restrictive red cell transfusion strategy in which the transfusion is considered when the hemoglobin concentrate is less than 7 g per deciliter or 70 g per per liter. Same thing. And that is a strong recommendation with moderate certainty. And then they just note this remark which just comments on areas of mo mo or more uncertainty which are gonna come to in a moment. Um There are certain subgroups of patients where people might think it needs to be a bit higher and they say possibly 7.5 for cardiac surgery, possibly eight for orthopedic surgery or those with preexisting cardiovascular disease. And interestingly, they don't comment on brain injury, which I'm gonna talk about as well. Um So now we we'll talk about that. So the the key issue is does one size fits all. Now, that seems very unlikely because is, as I said, transfusion is a treatment for a complication of a disease and that disease may be in very diverse patient populations ranging from a completely fit young marathon runner who gets hit by a car to an 89 year old with multimorbidity, um who's got sepsis in the ICU or something like that. Clearly, these people are not the same. So it seems very unlikely that one size fits all. And yet that's what the r that systematic review has done. It's put all the trials together which were in different populations. And a lot of these trials lump lots of different types of patient together within the trials. So are there clues that it might not be a one size fits all that are fits all? Well, there definitely are. So if we go back to the trick trial, that original Canadian trial, then one of the things they noticed was that when they did a post hoc analysis, so it wasn't preplanned. But in that 800 odd patient trial, when they pulled out the roughly 250 patients, which is a very small number in the way we do trials these days who had ischemic heart disease and they looked at the effect on mortality, then they got a very different signal. So this is a study that did that and you see it on the left where it says ischemic, you, these are patients with ischemic heart disease, most of whom had chronic ischemic heart disease, they weren't coming with mis that sort of thing. You can see, the mortality rate was higher in the restrictive group and it was the opposite way around in the non ischemic group. Um And that perhaps fits with the fact that they saw that bigger signal of safety with less blood in younger people uh at age less than 5055 cos they're less likely to have ischemic heart disease. So that raises the question, are some patients different or are some organs different in this case, the heart. So let's think about the critically ill or surgical patient with coexisting cardiovascular disease. And that is a lot of outpatients. Now, if we think about the heart, the first thing to say is that the coronary circulation is a bit different from most other circulations. So you remember, I told you that the overall oxygen delivery to the body is about 1000 about a liter a minute and we use about 250 mils a minute to have this oxygen extraction ratio of about 25% big safety margin. Now, in the heart, even the normal heart with completely normal coronary vessels, the oxygen extraction ratio is 60%. So the normal healthy heart is having to extract 60% of the oxygen from the blood, not 25%. That's the way the heart physiology works. And nearly all of that happens in diastole cos during systole, the pressure in the heart means blood doesn't go down the coronary art coronary arteries. Now, then think about a patient who's then developed coronary artery disease. So let's first of all, not think about acute M I but think about stable coronary artery disease. And that's sort of the patient in the middle here. Again, if you can see my cursor this one where they've got plaques that are narrowing the vessel. And you can then imagine that if the blood is desperately trying to extract 60% of the oxygen from the blood going down the coronaries, and then there's a coronary narrowing that slows the blood flow, it's not gonna be able to extract enough oxygen. So the heart in evolutionary terms, and physiologically is plausibly at much greater risk from anemia. And we have this concept of type two M I. So type one M I is where you get a plaque rupture and you get a blockage of an artery and the patient goes for a stent and all that sort of thing. But type two M I is where you don't have a rupture, but you have a supply demand imbalance in the heart, meaning that you get ischemia, but you don't get a classic necessary ST segment. And IM I but you can measure that with subtle ecg changes or a rise in troponin um concentration in the blood. The other possibility is that even in the absence of significant narrowing, you could have supply demand imbalance if you are really shocked. So a really severe patient with septic shock who is quite anemic, maybe they just can't meet demand because if the heart's having to work hard, cos the patient's in shock. So there's a plausibility that, that is important. So this is another systematic review. It's one that we did in Edinburgh a few years ago. And what we tried to do is extract from all the studies published up to that point, the subpopulations of patients who were documented as having coronary artery disease. And that's quite a difficult thing to do because it's often not very well documented. And this again is a forest plot which I hope you're familiar with. And what this showed was that if you look at the overall mortality risk, there weren't a huge number of patients, there was about 1500 in each group. Um and these were very varying trials in different populations. So there's a little bit of apples and oranges here. But if you look at the relative risk of mortality at 30 days, it was 1.15. In other words, 15% higher mortality with restrictive. Now, if you compare that with a systematic review of all the studies put together with all the patients in with almost the same studies but not pulling out the coronary artery disease people, then the more the relative risk was 0.86 it was favoring restrictive. So there's something going on here that in this subgroup, the signal might be the other way, doesn't, doesn't prove it. But on the available evidence at that time, it suggested these patients might be different. And when we pulled out M I rates as a key complication, what we found was that there was a statistically significantly higher rate of M I with restrictive practice. It was better to be liberal in patients with coronary artery disease. And that obviously fits with that belief that these patients are a bit different. When you looked at heart failure. It was a little bit the other way. But that's probably because this overlaps with TAO transfusion associated circulatory overload. So now let's so. So in patients with coronary artery disease, there are no large trials of patients with chro chronic coronary artery disease done yet. But the recommendations suggest that you should be a bit more liberal in those groups for this reason than most people would say a hemoglobin threshold of 80 to 90 not 70. So let's think about cardiac surgery now. So cardiac surgery is a little bit different, very high volume, massive use of blood in cardiac surgery. But in cardiac surgery, you're actually fixing the problem. You don't actually have another condition, but you're living with the problem. So there's now two large trials published and they both compared restrictive threshold with a more liberal use. They weren't as brave as 70 they used 75 and they both showed that restrictive is safe. So the threshold that's recommended for cardiac surgery is now about 75 g per liter. So you'd probably use a higher threshold in a patient with s stable coronary artery disease. Who's coming with something else who's maybe having a hip done or is in the ICU with sepsis. But if you're undergoing cardiac surgery, you wouldn't transfuse until hemoglobin was 75. And that's based on evidence with, with two large trials about 3000 patients plus. And what about acute MRI S acute M RSA? Different thing. That's a patient who's come in with a plaque rupture and coronary occlusion. So there's now two large trials published specifically in that group by far. The biggest is one called the Mint trial, which was only published last year, 3500 patients. It was a la very eagerly awaited trial and these trials compared a restrictive threshold of 70 to 80 depending on the trial with a more liberal use of 100 g per liter. And these trials showed no significant difference overall, but there was a trend to less M I and less death rates with the liberal approach. The signal was the other way, but in the trials, it didn't reach statistical significance. So people are looking at these trial results and putting them together now and it's very likely there will be some guidelines come out that in acute M I, we should be more liberal and probably think of thresholds of around about 90. But I IW watch this space, it will probably come out in the next year. Now, another area we're really interested in is acute gi bleeding cos it's not really an anesthetic condition, but it's very much an ICU condition. And there was lots of interest in gi bleeding um because there's strong associations between blood transfusions and mortality in gi bleeding and blood transfusions and b rebleeding after treatment in, in gi hemorrhage. But it wasn't, it wasn't clear whether that was causative or whether that was just a sort of epi phenomenon, a confounding effect that um sicker people end up getting more blood. And there's several trials now published and there are two larger ones compared a restrictive threshold, 70 to 80 with more liberal use and the highest quality trial and a systematic review of those trials. Uh Both suggests that lower mortality occurs with a restrictive practice. Uh And the recommendations are that you should not transfuse your patient with gi bleeding until their hemoglobin is 70 to 80 unless obviously they're bleeding to death. But many patients who present with gi bleeding are not like that, they need a little bit of fluid, then they stabilize, then you endoscope them and you treat their peptic ulcer or their varices. And interestingly, this signal was there for variceal bleed, not just peptic ulcer bleed. So we should be more restrictive um in all gi bleeding. Uh And that's what we see happening. Now. Now, one of the interesting things is that with gi bleeding, one of the key quality indicators. And what you're trying to do is get the earliest time to stopping the bleeding. In other words, the earliest time to endoscopy and we don't achieve that very well in the NHS COS of pressures. But if you give too much blood and particularly if you start correcting coagulopathy and liver failure as well, you will be giving large volumes of colloid fluid in the, in the form of blood and F FP. And that will expand the circulation and probably make the bleeding worse cos you will increase the pressure in the portal bit system and in the splanchnic system and probably cause the bleeding to get worse in the same way that we tend to be quite restrictive in trauma until we've got control of the bleeding. And what about septic shock? So, septic shock is our classic condition in the ICU where we think that we need high oxygen delivery to tissues. But as I said, our increasing understanding is that a lot of the organ failure is inflammatory rather than due to ischemia. So we have one large trial specifically in septic shock and a lot of the ICU trials included people with septic shock. And it basically was a redo of that trick trial. But in septic shock, but with the liberal group being a trigger of 90 rather than 100. And this is the trial, it was published a few years ago now. And those are the separation and hemoglobins they got. And these are the Kaplan Mayer survival curves. And you can see here that they are essentially identical, there was no difference in mortality. So we very much know that even in patients in septic shock, we should be restrictive and use a trigger of 70 as our default, maybe adjusting it for the presence of coronary artery disease and that sort of thing. And in the last year, we dramatically increased our understanding of uh what we should do in brain injury. Now, just like I explained to you that the heart physiologically and pathophysiologically is probably at greater risk from anemia than other organs. The brain is the same and the reason for that is the brain is in a tight closed box, our cranium, our skull so that if the brain swells, the pressure rises and the pressure will reduce flow. So just like a coronary artery narrowing can reduce flow, raised, intracranial pressure can reduce flow to the brain. And that could cause secondary insults to the brain in the form of ischemia. And we know that avoiding secondary insult to the brain is the key to improving outcomes from all forms of acute brain injury in the ICU. So, the traditional guidelines were that you should maintain a hemoglobin above 1000 but they were based on essentially virtually no evidence. And yet there were observational studies showing that there were associations between uh blood transfusions um and er adverse outcomes. So there was a it was a confusing literature. So we now have three trials all published in the last eight months which is fantastic. Emotion was a trial published in the journal which was just in traumatic brain injury. Train was uh a trial published in Jama which was in any kind of acute brain injury in the ICU. So it was subarachnoid hemorrhage and traumatic brain injury. And Sahara was a trial specifically in sub right noid hemorrhage published in in new just about three or four weeks ago. And they all compared a restrictive threshold with more liberal use of blood in the ICU. And all three of them showed trends, it was only statistically significant in the train study. But a lot of these trials were quite hard to recruit to and they were relatively small just about seven or 800 patients. But they all showed trends to a better neurological outcome in the liberal group. And the way in these trials, you measure outcome is a thing called the Glasgow outcome scale at six months, um which includes mortality but captures the brain function and the neurological status of the individual. And that's the way you do that. And all of these trials have shown trends towards better outcome. So although guidelines haven't been updated, it's almost certain that this will reinforce our practice that we should be more liberal in patients with brain injury in the ICU. So there's still some key uncertainties. We don't really know about elderly patients and patients with multimorbidity and frailty. And one of the key groups that we're studying is hip fracture because patients with hip fracture are old, they're often frail and they typically have multi morbidity and about 60% of them will have coronary artery disease. So there is a trial in hip fracture already. It was published a while ago now and it showed no difference in its primary outcome, which was actually a slightly odd mobility outcome. But a trend towards greater M I with restrictive practice, which was concerning and we're in the process leading from Edinburgh of a large trial and hip fracture, which will hopefully publish in about 18 months to two years to try and answer that question. But interestingly, the guidelines for managing hip fractures suggest a more liberal practice mainly for rehabilitation because these are elderly people have to get on their feet and get home. Um And um the general belief is it can't be good to have a hemoglobin of 70 or 80 when you're 85 with multi morbidity and just had your hip done. Um So we need watch that, watch this space for that one. And the other thing is impact on recovery. So it's one of my particular interests and we're doing a trial at the moment that we know that people recovering from critical illness remain anemic for quite a long time. Um because they often have inflammation uh and fatigue is the most prevalent symptom among ICU survivors and it goes on for weeks if not months and fatigue is the cardinal symptom of anemia. And so we're doing some work. But even though we know that when you're in the ICU, it's better to be restrictive or it's as safe to be restrictive. We're interested in whether treating anemia more aggressively after you leave the ICU promotes recovery and return to, to wellbeing and improves your quality of life. So we're doing two trials. The one that's hopefully will finish this year is actually looking at more liberal blood transfusion versus restrictive after leaving the ICU. And another one that we will be starting this year is looking at the impact of iron and epo to treat anemia after critical illness and see if that helps. So just very briefly, you remember, I showed you those pictures of red cells aging in the blood bank. So there was this key question about whether it mattered what the age of red cells was that you got. And there were lots and lots of observational studies which had very mixed findings. But a lot of them showed an association between receiving older stored red cells and adverse outcomes including higher mortality. For a long time. There was a belief that surely it must be good to get fresh red blood cells if you're really sick because they're gonna work better. But we now have four large RCT S over the last um 10 years, we were involved in a able in the UK. Um and they were in different areas, one in critical care, one in cardiac surgery, one hospital wide study and then transfusion was another critical care trial done in Australasia. And none of these studies showed a benefit from specifically transfusing fresh red cells. In other words, only maybe 678 days old from, from being donated compared to the standard stuff you get out of the blood bank. So that was very reassuring cos it would have been very difficult to do that um with blood banks because of the shortage of blood, but it gives us evidence that we just use what comes from the blood bank. And interestingly, the blood banks now because of red cell shortages, they're very good at managing blood stops. So that generally speaking, the age that the the oldest blood you'll probably get if you get a blood transfusion in hospital will be maybe about between 14 and 21 days, not in the twenties and up to 35 or older because they're using all that blood efficiently and using the older units to to make sure they don't sit on the shelf. So here's my last slide. Um It's a bit of culture for you from goer and Faust blood is a very special juice. It certainly is, but we need to know how to use it properly. And we're learning that really quickly and an anonymous um quote. So I have no idea who said it, but I liked it. Um The, the best transfusion is the one that was never given. But we do know that there are times when transfusions are needed. So we need to use blood carefully appropriately and I will stop there. That's why I last slide. I'll stop presenting. There you go. Perfect. Thank you very much, Professor. Um I think there is a few questions coming in in the chat. I'm not sure if you can see uh I can't see anything in the Q and A on my screen. Is it? Oh, there we go. Right. OK. Um Right. I'll take them in order then. Um So Leila's question, are any promising alternatives to traditional blood products you see becoming standard in the next decade? So there's possibly 22 ways of about answering that. So one is alternatives to manage anemia. So things like E Epo and iron. So I already said that there's a lot of research and interest in that area. So there will be, there are already lots of trials about iron and Epo and there are more trials coming. The issue there is that these work slowly. So they're never gonna be a treatment for acute anemia or bleeding. The other thing which I think probably what you're asking about is blood substitutes. Now there was a massive literature on blood substitutes going probably going back 30 years and there were two broad types of blood substitutes. Uh One was um fluorocarbons which carry oxygen and the other was sort of engineered hemoglobin molecules. And I'm not totally up to date with that literature, but there were lots of trials done and lots of different products and none of them were shown to be safe. In fact, quite a few of them were found to be harmful. And it just illustrates how our evolution has managed to produce such an effective way of transporting oxygen safely around the body without causing harm. Because all our attempts to engineer a hemoglobin uh that could be used substi as a substitute have failed. So it may be there's stuff coming, but I don't think it's gonna come in in the foreseeable future. There's a lot of work going on about um um generating red cells from stem cells and a lot of advances made. But I think we're a long way from generating red cells from stem cells at the volume and industrial level that we'd need to use in medicine. But again, I'm not, that's already my big area, but I think it's a little quite a way away. So that's probably that one. Oh I got, I got very cool. It's very nice. I need pretransfusion measures to minimize risk of tacko trolley reaction occurring. That's a good question. So, um so I'll take so there are two different things. So tret is transfusion associated acute lung injury. So that is thought to be an immune reaction to blood. And in fact, tret is uu under, it's not fully understood what causes tret, but it is probably um antibody mediated. Um and therefore, it's probably more related to the plasma than the red cells. So, tring after red cells is probably relatively rare because the plasma is taken out of red cells. It's much more common with F FP um when it occurs. But we exclude and treat F FP to minimize the risk of traveling. Now. And in particular, um we we don't use um plasma from um er women who've, who've had Children because they can potentially carry some of the antibodies that can be generated that are thought to potentially cause travel in other people. So there are interventions in the blood, in blood, blood banking that have reduced the incidence of tring. Um and, and also plasma is treated in various ways now to reduce the incidence of tring as well. Um knowing some of the um antibody mediated mechanisms that can occur. So that's, that's tring. Taco is largely about clinical judgment. So, Taco is giving too much volume to somebody. Uh and it's called taco and it's blood. So that is about clinical judgment and being sensible. So, the commonest cause of tackle I see in my practice is a patient with a gi bleed who has come in, someone's had a knee jerk panic reaction to the blood to, to the blood to the blood loss and given a load of blood and F FP and not followed the guidelines of not worrying about it if the patient's got a decent BP or hemoglobins down in the sort of seventies eighties. And those are situations where you can call the patient to go into acute pulmonary edema and getting in all sorts of problems. Um And that's the scenario you want to stop and think in an acute situation, how quickly should I give it the other way that to is reduced? I it is avoided is that if there's no need to give blood quickly, you give one unit at a time and you recheck the hemoglobin and that's what the nice guidelines say. You should always recheck the hemoglobin after every unit and that'll help you avoid giving it. So hopefully that's helpful with that one. So unless you inflammatory, inflammatory regenerated. Yeah. You know, that's a really interesting question, right? Er, if we can control the information we give blood. So that's a really interesting question actually, really interesting, quite, quite complicated question, but it's a really interesting one. So, um I, I'm not a rheumatologist or a, a chronic inflammatory disease doctor, but I think it's true to say that if you effectively control an a chronic inflammatory disease, you will get less anemia. So that's part of your answer. I think. So, effective control of, of inflammation in chronic inflammatory diseases will result in less anemia. So that, that, that's true, but it's not my sort of, that's not my specialty. Um I think your other question, I think the other bit of your question is possibly alluded to. Um if blood transfusion is given, can the ongoing inflammatory state affect iron utilization et cetera? That is a really interesting question. So, one of the things the trial that we're doing at the moment, which is transfusing ICU survivors or not, and seeing whether giving them a high hemoglobin with blood, improves their recovery and reduces fatigue and improves the quality of life. That sort of thing we are doing what's called a mechanistic study. In that study, we're measuring biomarkers in those patients. And there are several ways that blood transfusions could be harmful or helpful. So when you give a unit of blood, you actually give quite a big dose of iron to a patient because there's hemoglobin there. So if you have a patient who is iron deficient and you give them a blood transfusion, you will increase their hemoglobin, but you're also giving them some iron because those red cells will partly get re sort of eaten up by the spleen and release iron, which can be used. So it's a not the ideal way but you might be giving iron. So if the patient's iron deficient, you might help that the other thing that might be happening is there's some evidence that if you give a blood transfusion, you may be giving a sort of pro inflammatory insult because of all those changes that occur during storage. Um and if you give a pro inflammatory insult and you stimulate an inflammatory response, even if it only lasts for a few days, you will probably stimulate interleukin six production, which is the major inflammation mediator. As you probably know that will stimulate hepcidin production and that will reduce iron absorption and reduce iron availability. So, paradoxically, you might, might be reducing the ability of the marrow to generate red cells in the body. In other words, the patient's own red cells. So we don't know if that's the case. It's a hypothetical rate reason, but it might be the case that giving a blood transfusion actually suppresses the the person's recovery from anemia spontaneously. The other thing that blood transfusions probably do is cause some immunosuppression and the mechanism of that is not entirely understood. Some of it may be inflammation mediated, but some of it may be mediated by transfused white cells. And because we remove 99.9% of the white cells, now it may be less important than it was. But if you um make someone a bit immune suppressed, and there's a lot of literature on that, you will increase the risk of them getting infections and other complications. Um and that is a risk um which could prolong a patient's illness rather than, than reduce the duration of it or, or reduce how quickly they recover. Uh Have I answered your questions if we control the inflammatory state or? Yeah. So I, hopefully I've, hopefully I've addressed your question. It's a really good question. Uh Yeah. Ok. Ok. Have I missed any? Is that all of them? Uh, I think that's all of them. Right. Right. Yeah, that's good. Uh Thank you very much. Thanks for taking the time to speak to us tonight. I thought that was a really interesting talking to everyone's that we enjoyed that. Yes. Ok. All right. Well, enjoy the rest of your evening. Thank you very much. All right. No worries. See you all just now. Bye bye.