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My hand. Okay. Okay, good morning. Um So um still Doctor John Bogle, uh recently retired consultant in intensive care and anaesthetics uh working or having worked in the NHS of late and so date today, I'm going to talk about in our uh concept map referring to oxygen delivery. Always referring to oxygen delivery as the ultimate paradigm. We're going to talk about one of the three components which is hemoglobin. So just to remind you where we are in this the overall scheme of what I've been trying to uh lecture on. So we talked about the importance of how oxygen delivery is, the key to everything we can do and how the three components that make up oxygen delivery or cardiac output, hemoglobin, oxygen saturation, those constitute oxygen delivery and how we can always break these down into their sub components into their sub sub components. How whenever you're in a very chaotic situation and I repeat this several times because I think it's so important that you just simplify and go to the top and of those three categories, yellow are satisfactory, then you're okay. You can work out the details later. So today we're gonna talk about the second of those factors which is hemoglobin. Okay. So to summarize briefly today's lecture, we're going to cover two things. One hemoglobin, the transporter of oxygen and which everybody knows that it's a very well known role. Uh but also one that's not well known, not as well known to many of us. And that is hemoglobin, the flow regulator. So first let's talk about the transporter. So how important is hemoglobin for oxygen transport? Well, this was a, an article written by the recently passed Presidente of the American College of Cardiology, which I think summarizes this very well and so well recognized now. And that is the important discovery uh that anemia is very well tolerated provided that blood volume is maintained because the three factors that we've already talked about can compensate each other, especially cardiac output can compensate a low hemoglobin. But to do that, it needs an adequate volume. So yes, you will tolerate a low hemoglobin provided that you have the volume to allow the cardiac output to compensate. So just how important is hemoglobin for oxygen transport? Well, with anemia, your V 02 that you're V 02 is your your cells consumption of oxygen. So they are trying to produce energy which keeps us alive. It's all about energy and to do so, they have to have a supply of oxygen. And as long as that supply is adequate, then your metabolic process can continue. And that's what we call the V 02 okay. And if that will stay constant with an anemic patient because of compensate ori increases in cardiac output. So if the hemoglobin is less uh concentrated to carry the oxygen than it normally does given volume of blood, you will therefore increase the cardiac output. Therefore, more blood will pass through, maybe carries less oxygen, but more of it will pass through. So that will compensate. But the other aspect to help compensation is extractive oxy oxygen. And we'll come across that in a second. But we mean by that is that the hemoglobin which normally relinquish is or gives up one of the four molecules of oxygen can give a bit more if it's really needing to all that is to defend the cells capacity to produce energy, the V 02. So let's see what happens here. So if I take somebody and I start with the humana humana quits just another way of describing oxygen uh describing hemoglobin. Sorry. Um if you take somebody and you dilute their blood, so they are normal vel emmick, but they become more anaemic due to him. Oh, dilution, what happens to the cardiac output? And you can see if you start at a hematocrit of say 59 or so and you dilute. So again, they're normal valentic, but they're becoming more and more anemic. You can see that the cardiac output goes up dramatically as the hematocrit drops. And in fact, the hematocrit will drop to say 40% in this example. But the cardiac output will more than compensate, it will go up by 225% in this example. Now, why is this soap because of a factor or a concept or principal called pure thinning? What does that mean? Now, most of us know what a Newtonian liquid is, that's water. So water does not change its disc os itchy and it's constant. But blood is not a Newtonian liquid. Blood is a non Newtonian liquid. So for example, some of the better known examples of non Newtonian liquids are catch up. We've all assume we've all had the experience where you're trying to pour, catch up onto your plate and nothing comes and sudden you tap it a couple of times and suddenly it pours out more than you wanted. Um Also nonstick paints shampoo, these are all non Newtonian liquids as his blood. And what does a non Newtonian liquid do? And why is this important? Because we know that the viscosity or if you want to prefer the term gooeyness varies inversely with flow in a non Newtonian liquid. So the faster the flow, the less the viscosity and therefore the faster the flow. So you have a virtuous or a vicious cycle depending on your perspective. But it's a feel like a virtuous cycle, the faster the flow, the lower the viscosity, hence the more flow. So it just, it's a self fulfilling prophecy in a way. And this is important because by increasing the velocity uh in the small vessels, you decrease the viscosity, hence you increase the flow again. So it's always improving the flow in the small vessels. And as we know, if you look at blood viscosity, the factor that most determines blood viscosity is hematocrit. So as you can see here, as your hematocrit rises, you get an increase in even almost an exponential rise in viscosity. So for example, um uh a medical condition called polycythemia rubra vera has the problem of someone who produces excess red cells, uh unstiff related by the way. And so they have problems with thrombosis and blood clots. The same thing occurs in mountaineers. You go to high altitude and who over time as they acclimatize to this new altitude, they produce more red cells. That's part of a uh compensating mechanism to carry more oxygen. However, when you're in the, when you're an altitude, you always hyperventilate and you therefore lose a lot of liquid and you dehydrate because you're exercising like and one of the problems is if you ever get in a storm and you're in a tent and you can't move, your legs aren't moving and hence, you are very likely to get blood clots and even pulmonary embolus. So, excess blood uh large high hematocrit will increase viscosity as you can see here. So how low can you go when your chemo diluting Simponi? So, you kept the volume as normal. So we're not talking about HIPAA volume yet. We're talking about uh chemo dilution in this study. They took 32 healthy euvolemic chemo diluted patient's for volunteers. Sorry, not patient's volunteers. And they measured various cardiovascular parameters including and especially the central venous oxford content. And again, I'll come out to that in a second if you don't know what that means and blood lactate as a marker of cellular hypoxia. And they tried to determine what was the critical oxygen delivery as assessed by the V 02. So that's, that's the moment when the cells are not getting enough oxygen to perform the most basic tasks and lactate as a marker of that. So what is oxygen extraction? Just to briefly recall this because I think we talked about this at one of our previous lectures. And so um if you look at a capillary and a cell and we look at the arterial end of the capillary, you'll see that the hemoglobin which is fully saturated and has four sites for oxygen. So there are four oxygen molecules attached to the hemoglobin and you're 100% saturated because all the sites are uh are full of oxygen. So 100% saturation on the arterial inflow in this idealized uh cartoon as the blood cell, as the red cell passes by the cell, uh relinquish relinquish is it gives up one of its oxygen molecules so that the cell can produce energy in the form of A T P through oxidative phosphorylation. And then as it passes into the venous system, going back to the right heart, after having uh extracted, it's one molecule of oxygen, it has three of the four sites now occupied. So it's 75% occupied. So if you were to take a sample, so you were to take a catheter and place it into the right atrium, which is something we do quite frequently intensive care. At least you can take a blood sample. And you can look at the saturation, not of arterial blood alone, but also of venous blood, central venous blood. And that will give you an idea of whether the cells are requiring to extract more than one Oxford molecule. In fact, they can extract usually up to a maximum of about two. So they come back at 50% saturated. Now, because the tissues are all, they all have different metabolic rates. It's not quite so clean as 75 or 50. It's often somewhere between the two because there's a mixture of cells uh providing blood with different metabolic rates and hence different central venous saturations. But the central venous saturation is a marker of whether your cells are happy, whether they're getting enough oxygen to carry on, they're normal function. If you get a central venous saturation, that's too low. Says 55 60 62 that says to me that your cells are not getting the oxygen they need. And hence, they're having to extract even more oxygen from the hemoglobin. So it's a sign of like it's the last gasp. It's a warning sign if you like. So how let's look at this in this example where we reduce the hematocrit again, normal valentic and we've got uh four uh factors we want to look at. So we have the D 02, which is the delivery of oxygen to the tissues. And that's what we're all about oxygen delivery. We have the extraction, which is kind of your last um your last safety valve, your last gasp, if you're really in trouble with delivery of oxygen, which is not totally adequate, you can still extract more. That's an early, that's a sign that things are not going well. Your V 02 is the actual uh consumption of oxygen by the cells. That's what they need to produce energy and to keep the body functioning normally and lactate as a marker of the cells that are suffering because they're not getting enough oxygen to produce the energy they need. So, as you hemodilution again, normal polemic, your D 02 is okay, your extractions okay. The reason your D 02 is okay is probably because you're increasing your cardiac output to keep the delivery of oxygen uh at a normal level. Even though the hemoglobin is lower, your V 02 is fine. So you're getting more than enough oxygen uh for yourselves needs and your lactate is showing no signs of suffering. So you're okay because of the compensate ori increase in cardiac output. Now, if you were to make it even uh make the person even more anemic, and there comes a point where the cardiac output can no longer compensate, can't compensate endlessly. Then now you see your delivery of oxygen starting to drop and two counteracting that as a sort of your last gasp, your last safety valve. Now you're going to start extracting more oxygen. And that's a sign that you're really, you're, you're really getting into trouble and you have to do something, but that does work. It buys time. And so your vo to the amount of oxygen your cells are using is still okay and your lactate is still okay. So your cells are doing the job. They have to, they're getting enough oxygen by using all the various mechanisms that they can to provide that oxygen. So your D 02 is dropping and your extraction rates going up, but it can only go up to a certain point, say around 50%. And when you get to that point, you keep on him, oh, diluting. Your delivery of oxygen is now going down even further. And now you're extracting, which cannot, you cannot keep extracting. You can only remove roughly 50% of your oxygen from your hemoglobin that's really maximized out. And so now your VO two is starting to drop your cells are not able to produce the energy because they don't have enough oxygen delivered to them. And now as a marker of this uh of this anaerobic metabolism, your lactate starting to rise. And this is roughly around a hematocrit of around 10. That's a hemoglobin of around three or 30 depending on how you, what, what measurements you're using. And that's called a critical D 02. That's when you're starting to see an aerobic metabolism. And that's what we call the anaerobic threshold. And how far can you push this? Well, the lowest hemoglobin in the literature, at least that's been registered was this was during a liver transplant. There's another one very close to it after someone had his arm ripped off and it went down to 0.6 g per deciliter in the modern um nomenclature that will be 6 g per liter. So, uh so that's very, very low. Don't forget your normals around 15 g per deciliter or 100 50 g per liter. But what was important here was the, the treating physicians understood the importance of maintaining the circulatory volume and also they gave 100% oxygen because in this example, and this is something that's often underappreciated oxygen. Um at the cell level is always in the dissolved form, whether it's going through the plasma, the interstitium or the cell itself, the hemoglobin if you like is like a bank and it carries the oxygen to the near the cell, but the actual utilization of oxygen is in the form of dissolved oxygen. And usually it doesn't play a major role when things are relatively normal. But when you're getting down to such low levels, they will that oxygen will um play a role even clinically, I would say it seems to defy the theory of what, what is carried. So if you have 100% oxygen, there will be a little bit of dissolved oxygen and that will maybe just be enough to keep you alive. In this example, that's probably the case. So your volume and your 100% oxygen to keep the dissolved oxygen as high as it could possibly be. So when do you transfuse? And this has been a debate for years. So in the 19 forties, um due to some animal experiments, the almost arbitrary number and don't forget these are numbers that are either derived from animal experiments in the past or observation ulce studies of groups of people. And in the forties, the number, the magic number was 10 g of hemoglobin per deciliter or 100 g per liter. If it goes below 100 g, we used to say 10 g of deciliter, then you start to transfuse studies in the night. Several studies back there were many studies after in the in the late nineties, early two thousands seemed to suggest that a hemoglobin of seven D grams per leader or 7 g per deciliter was safe. And again, these were based on not on physiological data per se but on observational studies of groups of people. And don't forget today, we're talking more and more in medicine about personalizing treatment. So this is not really personalized, this is very much a group thing. So you might be an outlier in that group if you believe this number. But is this logical effect? And what I found interesting was it was a paper recently in the last year or two that had another approach which I found very satisfying because it refers to what we just talked about what they did was they used the central venous saturation. Remember that is the catheter that is placed in the right atrium where the superior vena cava two are pretty similar and it assesses your oxygen delivery. So if your oxygen delivery uh say is about 70 to 70%. And as we just said, that means that your cells are getting enough oxygen, they're not having to extract even more oxygen as a sort of last gasp. Then you're probably okay. And you can probably stay with that hemoglobin if the oxygen delivery uh is seen to be suffering. So you're central and saturation is low, say 60 62. Then that says you have got a problem of oxygen delivery. So then you better increase it by uh by transfusing. So this is more of a personalized way of looking at it. And to me, it seems physiologically more um more logical. So we all agree that giving that blood will increase your hemoglobin if you transfuse some, but that will improve oxygen, a tissue oxygenation, right? That's the goal to improve the oxygenation of the tissues. If you feel it's a need for that. Well, maybe, and this is a presentation given by one of the U K S and even I'd say in the world, he's well known as a trauma surgeon who is very interested in transfusion. And so let's hear what he has to say. The red blood cells that we give to patient's are not very good. We think that we give them because they deliver oxygen to the tissues. But the red cells that we give to patient's every single day in acute injury or acute emergency situations are very, very good at carrying oxygen. They are terrible at delivering oxygen to the tissues. I think that's really important because now we're coming on to the second role of hemoglobin and that is hemoglobin and it's a role that's often not appreciated. Hemoglobin doesn't just carry oxygen. It also is a flow regulator like an air traffic controller. So this is a little bit of a story. And so I do apologize if it's um seems a bit long winded. So, um when I was a trainee in Glasgow, I had a teacher who was a consultant, very, very smart man. And he told me young man, um he was a military anesthetist during the Mau Mau uprising in Kenya in the 19 sixties. And he was in charge of a blood transfusion system. And he said, young man, you will not know what it is like to give fresh whole blood. It's like nothing you'll see in this hospital setting that we're in right now because at that time and today, in fact, we use components, we gave red blood cells, pack cells, we gave platelets separately, we gave fresh frozen plasma separately, etcetera. Anyway, he was, he was wrong and he was right, he was wrong when he said I will never see this. I did. And he was right in that what I saw was unlike anything I'd ever uh had ever seen before, ever experienced before. I've done a lot of fairly major trauma transplant surgery, vascular surgery where there was a lot of massive transfusion. And this this case that I will tell you about now was like nothing I've ever seen before. And what was nice about this story is that these observations I'm about to describe were then followed up with a, a lab lab work that was done in the United States that might explain what we were seeing. So was observation and then it was uh experimental lab work which might explain this. This is not 100% sure, but it's very, very plausible. So what happened with me was that I was doing a locum in the middle of a mountainous and isolated region called the massive central and friend. And I was there for about 10 days and it's a small village in a small hospital. There's really not a lot there. And myself and a surgeon who was called in by a friend who was a professor of surgery in another university hospital. And we were together and we had nothing to do really very quiet. And one day we had someone who happened to be the mayor of this village who is a very important figure was involved in a road traffic accident. This was very scary because we're at least 4 to 5 hours away from help. So we're really alone. And this 50 year old mayor was brought in on a stretcher, he was awake and we took him immediately to the operating room and I put big intravenous lines into his arm. I knew that we only had um, two units of o negative blood and we were hours away from having any blood bank being able to help us out. I didn't like the way this man looked. I felt there was something about him that made me wary. We did not have a CT scan, we didn't have ultrasound. So, um, what I suggest we do is we do a peritoneal lavage that was one of the treatments you could do to determine whether you need to operate or not. And the surgeon was very reluctant because obviously he didn't have a lot to help him. But I, we trust each other, I think and he, he did that and we saw it was positive red blood came out. So we had to open him up. We saw an absolute catastrophic abdominal injuries, uh spleen, ruptured gallbladder, ruptured liver, pancreas was cut into on the column. There was lots of blood. We immediately or I immediately organized from through the help of the villagers, a blood donation scheme as you know, literally on site as we were working. So we were giving whole fresh blood and we gave 19 units of fresh whole blood to this map in glass bottles. And I won't go into how that happened cause that was not easy because we didn't have a system. You can't squeeze a glass bottle. I don't know why they used glass bottles, but that was quite a dramatic story. What what amazed me was given the quantity of blood that was, that was transfused. I would have expected to see what I usually saw. Someone who's a little bit cold around the peripheries, a little bit modeled. He wasn't like that at all. He was pink well perfused. He just looked really good and I just have never seen anything like that before and he did very well. And in fact, um he went on to carry on working as mayor. He was, he did very well and the ambulance arrived like four hours later, five hours later, just as we came off the operating room table. So what is going on here? Is it because it's whole blood, is it because it's fresh, whole blood is it? You know, we don't know what it turns out was. The US military has noticed through their various campaigns that because these campaigns are taking place in very warm countries, hot countries like Iraq and Afghanistan. And it's very hard to carry leaders of fluid with you in case you need it for resuscitation. They were using what they call buddy blood banks and they were giving one soldier with the same blood group or uh an appropriate blood group would give it to another soldier in the field. And they noticed the outcomes seemed to be better. And so the military experience that seemed to show that there were improved outcomes when they used whole blood compared to component therapy, excuse me. So now the military started recommending fresh whole blood for its survival benefit compared to component set therapy. Component therapy came into being in the 19 fifties after the second World War. So through the most of the, most of the things we know about blood are often do two military um military adventures. And so Korean War, the Vietnam where they started using components therapy. Um so so fresh whole blood was the way to go for the military. And now the civilian side in the United States at least is starting to push for whole blood. And even those that don't are saying we should use a components that are, you know, 1 to 1 to one ratio. Now, why would this be, could it be there are several possible reasons that whole blood is better fresh for blood is better if you look at component therapy. So a unit of red blood cells, a unit of platelets, a unit of fresh frozen plasma, you'll see there's 675 mills of plasma hematocrit of 29 only 88,000 platelets and coagulation activities only 75%. And importantly, fibrinogen is only 750 mg. That's quite important when it comes to uh coagulation. If you give a unit of whole blood, you've got 500 mils of plasma. So less volume um adequate is higher at 45 you get a lot more platelets, there are more functional, by the way, 100% of coagulation activity especially factors five and eight, which are very liberal and 1000 mg of fiber intake, which is very important. So could it be that's why outcomes seem to be better? But it could be something else. And I personally have got a funny feeling that it might be this based on some of the studies and the work that's been done mainly from Stanford in the United States. What is that something else? Well, if you look at the micro circulation and people are doing that more and more, you'll see that a blood transfusion um can either close down the microcirculation. So you may have a higher hemoglobin and macroscopically, you'll say you're carrying more oxygen, but microscopically looking at the micro circulation is getting worse. So what are we talking about here? So, if you have some severe anemia, the the micro circulation may be adequate. So you have a reasonable, if you measure the, the tissue oxygen uh oxygen pressure with P 02, it's okay. So you tolerate this low hemoglobin. As we've already said, if you now transfuse with backed blood to a hemoglobin of say 90 because adequate, you might see that the global hemodynamics are better. So you know, looking at your calculation of oxygen delivery may be fine. But if you look at the micro circulation and the tissue P 02, it's actually worse. So you look like you think you're getting better, but you're actually making things worse. So what's going on here? So let's try and take this uh back to something quite simple. We need fuel we need in the form of glucose, fatty acids, amino acids to produce energy in a cell with oxygen, we store fuel, some of us store more than we'd like to. But if oxygen is so vital, why don't we have oxygen tanks on our backs? That would kind of make evolutionary sense in a way. And in fact, there are some animals like uh certain cranes that overfly, the Himalayas actually have air sacs because the air is so rarified when they go over 7000 m or hiring. So, what does the Toyota car manufacturer have to do with all this? Well Toyota um, developed, I think it's in the seventies and eighties, something that was called just in time manufacturing. What that means is when they're making a car instead of having a warehouse where they have all their parts stock and they transfer those parts next door to the assembly line. What they do is they bring those parts in from the individual manufacturers of, of those various parts and they come in just when they're needed. They don't stop them because that's a waste of money and it's uh inefficient. So it's what they call just in time manufacturing. So they bring what they need, where they need it when they need it. And this kind of sounds like what we do because why would you want to do that? Why don't you want auction hanging around just in case it's needed because it's toxic when you look at someone who's elderly, if you could see my face right now, you can see I've got wrinkles because I'm older than you are. And that what it is basically is my um my tissues are undergoing lipid oxidation. So I'm becoming rancid meat. If you want to look at that way, that's why meat goes rancid. And there are lots of studies that have looked at this and they found that mortality is impacted by too much oxygen. I won't go reading them all, but there's, it's a very hot topic now that yes, you want to give enough oxygen, but you don't want to overdo it because oxygen is toxic. So maybe limiting the concentration of oxygen in the vicinity of the cells may be protective. So you want to give what you need when you need it just to the right amount. Hence, just like the Toyota system, you deliver the product or you deliver the uh the piece that's required to make a car just when you need it, you don't stock it, have it hanging around because that's in official and that might be doing. Um, so any Toyota copy the body, I don't know, but it's uh makes it interesting thought to bear in mind. So maybe this is our bodies version of the Toyota's just in time that because as we just said, options toxic to the tissues. So, hemoglobin seems to be the main controller of where oxygen is delivered. So it doesn't just carry it. It also decides where it goes. Okay. And how does it do that? Well, through the oxy hemoglobin curve. So if you have um a muscle, for example, that's hot because it's being exercised and its acid, then it will release the oxygen from hemoglobin. So it plays with the oxygen hemoglobin curve that's called the boar effect. But also maybe more important or as important, let's say, it controls the micro circulation and it couples the micro circulatory delivery of, of blood and oxygen to the needs, the metabolic needs of that self that those tissues. And I think that's what's really interesting. So how would it do that? Because red cells seem to be the oxygen sensors and controllers of where the blood goes. And we know that fresh blood and this has been shown in many studies, fresh blood and I emphasize the word fresh will increase what they call the functional capillary density. Basically, it opens up the capillaries, stored blood does the opposite. It clamps down the capillaries, it causes them to constrict and hence does not deliver the oxygen and hence the cells that are near the capillaries maybe lacking in Oxford. So fresh blood improves the flow, stored blood decreases the flow. So the physiological role of red cells is not just to carry oxygen, it's also to match flow to metabolic demand regionally. So if red cells match flow regionally to metabolic demand, how does it do it? It probably does something that uses something called S 90 S nitro sal hemoglobin, snow, snow hemoglobin, which is formed in red cells in proportion to local hypoxia which will cause local visit debilitation. So if you have local um if your cells are using oxygen, they will reduce the pressure of oxygen around the cells that will cause local hypoxia. The red cells will sense that well use its snow and hence, well vasodilate. Hence you deliver more oxygen. If on the other hand, your cells are not using oxygen and oxygen levels were to rise next to the cells in the tissues, then that would reduce the production of snow. Hence, the capillaries would not dilate but would constrict. Hence, you delivering less oxygen. There's no point in delivering oxygen to an area that has too much oxygen because the cells are not using it. So how good are stored red cells at delivering oxygen to the tissues? As you heard, professor, uh the trauma surgeon earlier in the video. Well, let's look at this, let's look at microvascular profusion with stored red cells. And don't forget it's a microvascular perfusion which is the ultimate site where you want to deliver your auction too. So here's what we look like. We use fresh versus stored blood. That's the arterial oxygen tension. So they're pretty similar in the arterial side of things. But now let's look at the tissue side and you can see stored blood delivers a lot less oxygen uh compared to fresh blood. So what happens when you store blood? There's several things that happen. Some of them are very well known. Some of them are not. So we all know that 23 D P G is reduced um when you store blood and that reduces the ability of the hemoglobin to release oxygen to the cells at the tissue level. So reduce TB to three D B G. We all know that I think it reduces the ability of hemoglobin to release the oxygen at the cellular level. So it holds on to it, which is not what you want. But what's interesting is that this reduction in oxygen delivery is seen before you see a decline in 23 D P G. And we've always been taught that to three D P G was the reason that uh that bank blood is not, is not fantastic at delivering oxygen to the tissues. It transports it, but it doesn't release it. But this, this reduction and delivery occurs before a do client in 23 D P three. So that can explain everything. What happens is that storage alters the red cells, oxygen dependent ability to vase a regulatory um to to visa regulate uh in relation to the oxygen level the tissues. So just we described a second ago, red cells can either vasodilate or vasoconstrict depending on the amount of oxygen in the tissues or near the tissues. And this storage alters that red cells ability to be an air traffic controller. And the reason is because it's lacking in snow, which is the vassal dilator through which d saturated hemoglobin is coupled to the regional metabolic needs of the tissue and hence alters flow. So, snow seems to be the missing link here. So what happens with um if you store blood? So what they do is they took 500 mils of blood uh from 15 healthy volunteers in this study. It was published in the National uh it was proceedings of the National Academy of Sciences. So it's quite a prestigious journal. And what they found was that snow in red cells decreased rapidly with blood that was withdrawn from these volunteers. At the same time, vasodilatation by stored red cells was depressed. That's not unexpected based on what we've just said. So how long before fresh blood becomes old? And this is really fascinating and the reason this is fascinating is that there have been many, many studies um by some very eminent scientists who have looked at is old blood less good than fresh blood. The problem is when you read the definition of what is fresh blood, their idea of fresh blood can be anything from a day two, a week old that's fresh compared to old blood, which maybe 30 40 days old. The problem is the definition of fresh blood is inadequate. Why let's look at this, if you take, if you measure snow, which seems to be this very important component of, of the control of flow to the cells, you can see it, it decreases immediately if you look at the ability for it to vasodilate in, in the face of tissue hypoxia, and you're trying to marry it to the metabolic needs of the tissue, you can see it does the same. So the two are very closely related. But what's really important to note is this three hours, snow is a volatile agent, it's volatile. So as soon as you remove blood from the, in this case, the volunteer, the snow dissipates. So if you say we're gonna look at old blood versus fresh blood, and our definition of fresh blood is a day old or even seven hours or eight hours old, definitely a week old. That is too late, that's not fresh because within three hours you've already dropped your snow, hence your ability to vasodilate in the face of a low tissue explanation. And hence you'd want to open up the circulation for more blood. The second thing that the last thing I'd like to say is that um hemoglobin is uh is important, but hemoglobin also has a dark side to it if he know hemoglobin normally is enveloped in a red cell membrane, if for some reason, it is free. So you have Hamal Asus. And one of the examples is a is sickle cell disease or sickle cell, uh anemia or whatever cause of free hemoglobin. It has a dark side and that is, it acts as a sponge and it will soak up the nitric oxide, which has got so many important roles to play, including vasodilatation, platelet, adhesion, etcetera. And it soaks this up. And if it's inside the cell, as we just saw, it's absolutely vital to control flow to the tissues that need the flow. If it's on the outside of the cell, it's toxic. So you want that cell surrounding that hemoglobin. So here's an example of this. If you look at this um this cartoon of what happens in a patient who has sickle cell disease. As an example of height amal icis, you can see that the nitric oxide is absorbed to this free hemoglobin. So it sucks it up like a sponge. So it's not available for its other actions. And you get things like uh with a decreased nitric oxide bioactivity, you get pulmonary hypertension, ulcer, Adrian priapism strokes, acute chest syndrome, pain, crises, vascular occlusion, etcetera. So you want that hemoglobin to be enveloped in that cell because otherwise you, you're going to get into trouble. So to recap what we've said, hemoglobin's got two roles. It's a transporter and we all know that and that's the main um the main rule that we think is hemoglobin's uh primary function, but it also has the very misunderstood or not understood or not appreciated role as a flow regulator. It's an air traffic controller. If you, like we said that you can tolerate low hemoglobin levels provided that you have adequate blood volume. So if you have someone who's euvolemic and anemic, this example him a dilute, you'll see that the cardiac output will increase dramatically relative to the drop in hematocrit. So it will more than compensate uh for a low hemoglobin. We saw that how, what happens if you progressively dilute and how you have a series of compensate ori mechanisms, whether it's through the increase in cardiac output or the increase in oxygen extraction. And so your cells are getting enough to continue their central uh function of providing energy. So the V 02 stays okay and there's no increase in lactate as a marker of anaerobic metabolism until you get to the point where you can no longer compensate. And then you start getting a drop in uh in V 02 and an increase in lactate, which is a sign of uh anaerobic metabolism, that whole blood seems to be um advantageous compared to uh component therapy. And so more and more hospitals now are using uh fresh whole blood, whether it's fresh or not, it's in the question, the whole blood. And for the reasons that we just described how fresh would maybe uh very different, too old blood because of its loss of it's volatile component, which is S N O and that could take place very rapidly. So if someone is talking about fresh blood, they're talking about very fresh blood. And in the example I gave in my story, we were giving blood literally from arm two arms that was very fresh, similar to what they saw in the military where they noticed the same thing. So this makes sense. This is what's interesting, it's totally plausible from a biological point of view and from an experimental point of view and it could be because it acts on the micro circulation because you don't want oxygen hanging around cells because it's toxic and you don't want it too much oxygen, but you want enough when you need it where you need it. And if you have oxygen, if you have hemoglobin, that's not uh it's not within the red cell envelope, it's membrane, then it actually has toxic effects by sponging up nitric oxide, hence causing thrombosis and vaso construction. And that really is uh that's the civic for today. So if you have any questions, please uh don't hesitate. So does the S N only can be a challenge? Isn't? Oh, I'm sorry, I can hardly hear you. Hello? Can you hear me a little bit? There's a bit of an echo which makes it difficult. Okay then. Yeah, I can, I can just go here, you go ahead. So it's the sl oh that makes all the difference. Well, it's, there are many components in this. What I was trying to say was that we all concentrate. Um We all know about the ability of hemoglobin red cells to transport oxygen like like a bus carrying people to one point to another. But what we don't appreciate is what seems to be the ability of oxygen to control where that blood goes. That's what really seems to be exciting, but it makes perfect sense. It's an air traffic controller. Do you want to plan that way? Uh I also had a hardest to nestor leads to method of transfusion. On the only days when they're transfusion had a few is being taken into consideration. So the Africans and the Americans have their own natural of transfusion. The Americans went with the plasma monitored and the Africans went with the RBC difference. Uh as I suspected the plasma matter can't be very fatal compared to the African uh medical system today went with the obviously. So it was then and that people learned transfusion methods that the IV sees uh exactly recruit transfused. Yeah, I'm sorry, I'm really having a hard time hearing you, but a lot of echo there. Um I think one of things that's very interesting about this S N O business is that if it, you know, I can't say it's 100% proven yet. Um But it's, it's very fascinating and it makes a lot of sense. But um if it turns out to be true, what is really fascinating is it means that maybe you can take quote unquote old blood bank blood, whole blood and percolate S a know through it to convert it into fresh blood. I don't know if that's possible or not, but that's what some people are suggesting. But what your, if I understood what you're saying about difference between United States and Africa. I think what's interesting is a lot of, a lot of what we do today in trauma and a lot of what we do in terms of blood transfusion seems to be, um, inspired by or instigated by the military. It's always been that way and what the military have noted was during the wars in Afghanistan and Iraq, the, the conditions are obviously very, very hot and the soldiers have a lot of gear to carry with them. And the one thing they didn't want to do is load them up even further. So they didn't want to give them even more, um, even more, uh you know, bags of ringer's lactate or whatever. And so they use their own colleagues as blood banks until they could evacuate these soldiers. And they noticed that with this fresh, whole blood and they were focusing mostly on the whole blood side of things that the outcome seemed to be considerably improved. And so the trauma centers in the United States and then now it's even the American Association of Blood transfusion are saying maybe we ought to be using whole blood as opposed to component therapy. There is different advantages to that. But the other side of the, or the last piece of this equation, maybe the fact that it's not just whole blood, which is I'd say probably best, but it's also fresh, whole blood because that's the thing that they didn't notice is that this, this is not just whole blood, but it was blood that was given immediately to their, their military colleagues. And I think that's what I find interesting anyway, that's, you know, keep an eye on this. It's gonna be interesting today. No other questions. Can you hear me now? Uh just about, go ahead. What I was saying was in the early days of translation therapeutic. Uh Both the military in the Africa, the African military uh they were doing with the RBC uh in the transfusion therapy, they were using rbc's whereas us military was using plasma, which turned out very bad for them because then they realized that the obviously part was the main component for the transfusion. This is for transfusion. I'm saying uh you know, it's hard to answer that because most of the Americans used whole blood in the Second World War. They did use plasma as well. But don't forget what we said right in the beginning was that you can tolerate anemia to very low levels, provided that volume is maintained. And then if from what you're saying, it sounds to me like if the American military were using plasma, it was more to keep the volume maintained as opposed to just giving red cells. And between the two, I think it's probably more important to keep volume maintained because you can tolerate very low levels of anemia as you saw. Um but you will not tolerate uh any anem a anemia if you're hypovolemic. So you know, I don't know for sure what you know who's right, what's wrong? Who did what? But it makes sense to me that you definitely want to maintain your priority has to be volume first. There is a question in the chat. Um So uh Tiro is asking what the conditions that can get H B out of the cell. Oh, okay. Right. Well, um, any form of uh Hamal icis. So we just use the example of sickle cell disease. Uh There are various autoimmune diseases. There's something uh called ma ha micro angioscopic hemolytic anemia. Uh There are transfusion reactions. Uh gosh, I'm trying to think there's uh even some of the machines we use today um, can cause hemolysis whether it's, you know, blood transfer, uh hemodialysis ECMO. There, there are loads and loads and loads of possible causes of, of hemolysis but any form of Hamal icis will release free hemoglobin and that free hemoglobin can actually have quite a few negative effects because of the fact that it absorbs nitro coxa. Anything else? Does anyone have any other questions you want to write in the chat? So I can read out for you otherwise. Should we end it here? Yeah. Okay. Okay.