Lactate friend or foe Dr Vogel
Summary
In this on-demand teaching session, Dr. John Bogle, a recently retired intensive care doctor and anesthesiologist, will be exploring the subject of lactate - is it a friend or foe? Dr. Bogle will examine how lactate relates to prognosis, metabolism of lactate, and why it is strongly linked to outcome. He will also discuss whether it is a waste product, and how lactate is used as a marker of a critically patient’s prognosis and guide treatment decisions. Join this enlightening session to learn more about this misunderstood subject!
Learning objectives
Learning Objectives:
- Explain how elevated lactate is associated with a poorer prognosis for critically ill patients.
- Describe why lactate is not always a result of poor oxygen delivery.
- Explain the differences between aerobic and anaerobic metabolism with regards to lactate production and use.
- Explain what the Cori cycle is, and how it impacts lactate levels.
- Recognize the speed and energy efficiency associated with lactate metabolism.
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Computer generated transcript
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The following transcript was generated automatically from the content and has not been checked or corrected manually.
Okay, good morning. Um Again, my name is Doctor John Bogle, a recently retired intensive care uh intensive care doctor and anesthesiologist, anesthetist in the UK. So, um today we're going to talk about a subject that most people think they understand and I may surprise you with some of the, some of the things I'm about to tell you. So, the subject is lactate and we want to know, is it a friend a PFO or is it just misunderstood and the outline of today's talk, which I'll go over just once is how it relates to prognosis. Is it due to sell their hypoxia? Which everyone believes. What is the metabolism of luck tape? Why is it so strongly linked to outcome? Is it a waste product? And lactic acidosis? Is it real or is it a myth? Okay. So everyone knows that raise lactate is almost always bad news in the critically ill. So we're talking not about the kind of patron who sees a G P who's not too unwell. We're talking about the severely ill critically ill person. Is this true? Well, given, I think it is. Yeah, it is good. Absolutely. You're absolutely right. Lactate. It's one of the markers that's the most uh widely used to try and generate a prognosis for a patient and to guide our treatment. So, what is, uh this is just one of many, many, many studies over the decades, I'm just picking this one study up. If you look at lactate on the x axis and you can't sub survival, we're not sort of dying either. You can see that there's a really linear relationship between lactate, even a slightly raised lactate and your chances of dying in hospital. So it's a really strong marker of something going bad, going wrong. So you want to follow that. And um this was an interesting, um one of several interesting studies that I've seen that shows how it's so much more, it's a compliment to vital signs when you're trying to establish how sick and how risk uh at risk of patient is. So if you can see on one access, it's, you've got systolic BP. So we know if someone's hypertensive, that's a bad thing we have on the other access, the level of lac tape in this study that just shows a cut off of 3.5 so low, but maybe still, you know, above normal and high or very high. And we look at that how that relates to mortality. So you can see the mortality is about, I don't know, 567% if you have a slightly raised lactate. But with a normal BP, if you have a low BP, then you're mortalities goes up considerably. On the other hand, if you have a normal BP, it's a systolic BP and you have a very raised lactate. Mortality is very much higher. So even if you have a normal BP, but raise lactate, your mortality is considerably raised. And if you have a low BP and a low lactate, you're in deep, deep trouble. And what's interesting about the normal BP and high lactate is you may have something called cryptic shock. So in other words, someone maybe in shock and I still have a normal BP and without going into too much detail, I was involved in a court case as a defense expert of someone who was accused of not recognizing a sick patient who eventually died. And the, um, the prosecution said that the patient was in cryptic shocked because they had a high lactate that was ignored, but a normal BP which reassured the person being accused. So lactate and cellular hyperoxia. A raise lactate is bad news. We agree because it always signifies cellular hypoxia, right? Uh, at the cellular level, it should be normal because it could be produced it or be generated in some other form. Well, I'm amazed you said that because you're absolutely right. Let's put it this way for decades. We have and we are still taught that a highlight eight equals um poor profusion, hence, cellular hypoxia, hence lactase produced. And that's what we're taught. And many, many teams have tried to uh improve on mortality by not just raising auction deliberate to a normal level in a sick patient, but super normal levels because it's gonna, you know, uh prime, prime the pump if you like get the cells to start producing and reducing lactate and producing uh 80 p energy. Now, in the early phases of someone who's severely ill, there may well be uh reduction of oxygen delivery. You please do not misinterpret what I'm about to tell you. I'm not saying to ignore oxygen delivery. It's just that the model we've been taught for decades, but this is always due to poor option delivery seems to be not the case. So this is one study again, of many studies that looked at the probability of survival in someone who comes in and who's being treated as a control group, just routine treatment. So they're, they're getting the basics right? But they're not doing anything more than that. So if you had a low BP, we get the BP to normal but not, we're not trying to push the the production of ATP by increasing oxygen delivery to above what is considered normal and then the super normal group. Absolutely no difference. And this has been thrown over and over and over again. So maybe sell your hypoxia is not the main cause of a race lactic. And what about if you look at someone's um tissue oxygen uh in the interest ish in this is muscle, forearm, muscle of patient's with who are normal. So, volunteers or patient's who are septic and you can see the normal person has a P 02 because whatever it is in this case, 12 m of mercury, 10, 12, that's normal in the next to the cell. This is right. They use special diet and now you look at someone with severe sepsis. So you think it be lower in the model that we've always been taught, but in fact, it's higher. Excuse me. So this idea that we're lacking in the cells are lacking an oxygen, hence producing lactate um is not always the cause. It may be sometimes but not the majority of people do not have cellular hypoxia based on the studies uh we've seen recently. So if raise lactate in critical illness is not due to several, your hypoxia, then what does it do to before we go into that, we have to look at something about lactate metabolism. Now, I don't want to bore you with all the biochemistry. So I, so please do bear with me. But you have to understand some of this to make sense of what we're talking about. So here's the cell and you've got the side this or and in the cell, you have the mitochondria, you have glucose that will be transported by glut, which is a glucose transporter molecule protein into the cell. And using PFK, which is phosphofructokinase, which is a rate limiting enzyme you'll produce pyruvic. Now, all this must look familiar to you. The pyruvate will be transported into the mitochondria where using pyruvate dehydrogenase, these, you'll produce ass taco A and goes into that goes into the citric acid cycle of the Krebs cycle and it will produce through the respiratory train. Um 36 80 ps, the mighty that's called oxidative phosphorylation system clocks fos so 36 80 P S and I ATP as you know is a sort of a packet of energy that we use. We store energy in a teepee or using instead of going down the path to going into the mitochondria, we stay outside the mitochondria and stay in the side of soul. And we could produce through the use of the enzyme lactate, dehydrogenate. We produce lactate and that's called fermentation. If you like that does not require oxygen. In that case, you produce only two ATPs through just pure gal I Colaces. So, glycolysis on the outside and um oxidative phosphorylation inside one produces 36 80 piece that's very, very efficient. And the other is only two lactate. However, can also be used to be as a as a fuel, can be, it can be shuttled in to the mitochondria where it will be oxidized as well, just like part of it, but it also can leave the cell or it can go into another cell. So lactic can be, it's kind of a Swiss army knife. It can be used inside your own cell or could be moved to another cell so I can go I/O. So it's a general purpose fuel if you like. No, let's look at the two types of metabolism quickly. So there's aerobic. Do you have enough oxygen in your cells or around your cells? In which case, we just saw glucose goes to pyruvate and 90%. So nine out of 10 go to the Krebs cycle, but one out of 10 goes to lactate. So the ratio will be say 10 to 1. So roughly that order of magnitude, so most of the like most of the pyruvate will go to the to be oxidized in the Krebs cycle to produce 36 80 P S and one out of 10, roughly that certain ratio will go to lactic. If you have something that accelerates your glycolysis iss you'll keep the same ratio. But you'll, as you can see the larger arrows, you're going to basically, you know, really rapidly produce more pyruvate, which will proportionally produce a lot more lactate. If you're in an anaerobic situation and you, you have to ferment. In other words, you can't use the oxygen because there is no oxygen or less oxygen than required. Then what happens here is that the glucose goes to pyruvate, but it can't go to the Krebs cycle because you need oxygen for that. And so all it can do is produce lactate. And that lactaid can then go to something called the Corey cycle, which is in the liver and to a degree in the kidneys. And both of those systems, whether it's x glycolysis, especially accelerated glycolysis, ist or the anaerobic system will go to a liver mainly and that will produce, eventually lactate, will go to pyruvate the glucose and the glucose in the liver will then be used by organs that require glucose like the brain. So it's some ways it's um it's a convert, it's converted, you're lactics converted to glucose. So it's, it may spare um spare the other organs that um that would use glucose normally. And so they would use glue lactate instead of glucose. So, basically, lactate seems to be in the center of everything here. So on the left hand side, you have the normal aerobic metabolism. And if you have for some reason, and we'll talk about this in a second, maybe accelerated massively or if you're in an anaerobic situation, then you can't um use the Krebs cycle. In which case, you only rely on lactate. An MCT is um on a carboxylate transporter for those who are interested. What MCT means. Now, let's look at energy predict. This is something that's often not appreciated. We know that lack the power of it's very efficient and through the oxidative phosphorylation, it will produce, we just said 36 ATPs. If it goes down the lactate pathway, remember, we said out of every 10 higher rates, one will go to lactate. In this case, it's very fast. It'll only produce too ATPs, but 100 times faster. So, yes, it's less sufficient, but it's really fast. And so, um, I don't think that producing lactate is sort of a poor man's way of making energy ATP because yes, for a given period of time, you will, you will produce less um ATP per pyruvate, but you'll produce it 100 times faster. So for a period of time, you'll get the same amount of ATP. So basically, what I'm saying is that even without oxygen, you can produce energy. So in critical ills, what do we um what do we know so far? Well, we definitely just said we agree with this lactate is always any study will look at this will say it's definitely clearly associated with the risk of death. So you see lactate bad news you want to, you know, think about why is that lactate up there? Hyperlipoproteinemia is infrequently due to a poor delivery of oxygen to the cells. Now, that's important because we've always been taught that that's what it signifies. It's poor oxygen delivery. And in fact, the recent studies seem to suggest that may not frequently be the case, it could be, but it's not frequently. Now, this is what's important stress, whatever kind of stress we're talking about stress. Can be an infection, it can be exercise, anything that will stress or your body considers stress will release catacholamines and the catacholamines will lead to an increase in aerobic glycolysis. Remember we just said we had the glyco lytic pathway that was aerobic, but it could be accelerated and it's accelerated the proportion of pyruvate to collect eight, still 10 to 1. But you're going to get a lot more a pirie and a lot more reflect eight. And that's what's happening here. It's a very fast way of producing energy and then that will produce hyperlipidemia. And what we know today is that lactate is an essential energy source for most, if not all the tissues in the body. So it's not just a waste product, it's a central energy source and it probably is a vital survival response that has evolved down the generations. So lactate is not a sign of a lack of oxygen. It means that you are under stress and this is your body's way of trying to survive that stress. So just to prove this to you, if you can see here, if you have lactate and you, you're making flat on the Y axis and you start an infusion of adrenaline in volunteers, you'll get a massive rise in like tape. And as soon as you stop the infusion of adrenaline, you'll get a drop. So if I give you adrenaline intravenously or if your body is producing it endogenous lee due to stress, you will get a rise in lactate and that's not meaning you're lacking an oxygen. It means that you're stressed and hence producing lac tape, producing lactate secondary to adrenaline. So let's look at the cell again, we'll get off the cell, your side of things in a second. So we look at the glycolipid compartment, there's glycogen, I'm just trying to show you how the adrenalin works here. So there's adrenaline and you have a receptor and that receptor will uh except adrenaline and that will cause the release of cyclic amp. Now, I know there's a lot of biochemistry here, but it's just important to get the concepts correct. And that cycle campy will cause the breakdown of glycogen into glucose. But at the same time, it will stimulate the sodium potassium pump, which is vital for the cells well being and that's an energy um consuming pump. Hence glycolysis now will be providing the energy needed by that pump. And so glycolysis will produce pirate day and hence ADP, which is the uh the molecule that's lacking in energy becomes a T P triphosphate and that produces energy. That's, that's your energy, your A T P and that ATP then goes to the sodium pump, sodium potassium pump and it provides that the energy it needs to keep working and keep yourself healthy. Now, part of it, if he said part of it will go to lactate and we said 10 to 1 of the healthy cell that has oxygen that lactate can be used in the cell itself. We saw earlier, it can be used as a fuel in the Krebs cycle or it can be pumped out of the cell and it will be used as a fuel in other cells or other organs. And if we look at the mitochondria with the oxidative compartment, you know, your mitochondria is going to be producing uh more ATP per per molecule. But on the left hand side, in the Glyco clinic compartment, we told you was about 100 times faster. So it's really fast. And the mitochondrial department, you get a lot of like you get a lot of oxygen, a lot of ATP 36 per molecule, but it's a lot slower. So you got two systems here. You can see it's a really clever way of trying to make sure you have enough fuel to keep the cells working over. So we have a new paradigm. So this old paradigm that lactate means lack of oxygen is not true. It can be sometimes, but it's not always. Trust me. I should say it's not always true. So shock induced hyper lactate India is infrequently due to sell your hypoxia. Usually this is the important bit. It's a marker of the stress response and it plays a major protective role because it's a universal fuel. That's why I'm lactate is so strongly linked to outcome. Not because lactate is bad. It's because it's saying to you that your body is trying to react since whatever causes a stress like an infection, for example. And that's your body's response by producing lactate. So we just said we're just going to reiterate this. So lactate is a metabolic waste product, right? Well, wrong. It's got multiple functions. It's incredibly when you read it to this a bit more, how important liked it is for multiple roles in the bucket. As we just said, it's a very important kind of universal bioenergetics fuel. It's an intermediate metabolite which governs protein synthesis and mitochondrial Sinensis. And it's a signaling molecule. So it's got multiple complex roles. So it's not just sort of the, the garbage we take out and we don't have enough oxygen. It's not just a waste product quite the opposite. It's a very important universal bioenergetics fuel and it has other roles as well. So we just said it's in the central fuel. So how does that work in the muscle? For example, muscles are interesting because they, we always assume when you run and your calf is on fire, it's because you're producing lactic acid because you lack oxygen. Not true. So your lactate producing your muscle will be used by muscle cells themselves. And that's called the interim cellular shot. And if we look at that a little in a little bit more detail, you can see here that it's used for glycolysis and it can be used for oxidated phosphorylation as well. It don't forget like it goes into the mitochondrion becomes pyruvate. So it can be used both for the Krebs cycle or through the glyco lytic pathway. It can go from cell to cell. So you have an intracellular cell to cell lactate shuttle and it can go to the liver and kidneys and produce glucose, gluconeogenesis, the Corey cycle. So you can see like is being used all over the shop, all over the place. So this is just a quick uh cartoon if you like, do you have stress, for example, severe exercise or an infection? And what happens to your body when you have a severe infection, you become cata bolic, we know that. So your muscles will produce glycolysis iss and that will produce black tape which will leave the cells, some of it will use, but some of it will relieve the cells to go to the liver. You'll break down your protein what's in credible. And people don't appreciate this. When you're severely ill in intensive care, you can lose through the cata bolic process. You can lose up to a kilogram of meat of muscle per day. And there are studies which are quite graphic showing a plate of what looks like beef stew, raw beef. You're losing a kilogram of that a day in the most severely patient's because you're breaking down your, your muscle, your adipocyte, it's your, your fat will be, you'll have the policies. And so all these um building blocks go to the liver and what do they do? They produce glucose, but lactate the big one. And the glucose you can go to organs that are not dependent on insulin because when you're severely ill or stress, you become insulin resistant and that goes to your brain which requires glucose. So in some ways, it's sparing um the glucose that would be used in other organs to, to serve the brain or red cells or importantly, white cells and lymphocytes because those are your immune uh immune agents. So they're needed for immune response. So those vital organs are going to get the glucose independent of whether you're able to use insulin or not. And the organs that normally require insulin in the severely ill will be blocked, you become insulin resistant and so they don't go to those organs. Hence, um you get insulin resistance. So that's your body's response to stress. We look, just look at a couple of organs um and how they react. So, during shock, your heart will oxidize lactate from most of its energy needs. So at rest, your heart mainly uses free fatty acids, not glucose but free fatty acids and about 80% of your energy for your heart muscles. Your maya sights your cardiomyocyte rather uh come from free fatty acid oxidation tree about 20% to lactate. But when you're stressed and exercise as well as stress is a form of stress, 60%. So you're massively using much more lactate, your heart can suddenly convert over to electric. So it's a really great universal feeling. The brain again at rest, 93% is glucose. You really need glucose and a little bit of like tape. But when you're under stress or exercise, it increases the selected update. In fact, in some recent studies, looking at traumatic brain injury, some people are experimenting by giving patient's lactate as a preferential fuel for the sick and injured brain. So the lights, the brain becomes a latte consumer, not a producer only, but more of a consumer. And muscle. As we just said, um is using a lot of it's producing and using a lot of lactate. In fact, if you have one leg, exercising another leg at rest and they're sampling, you'll find the exercising leg using lactate and the resting leg. This is experimental obviously will be producing like tape, but it's not do the hypoxi. That's why not, why you get uh burning muscles. Because what happens you get catacholamines released when you're exercising form of stress, which increases lactate production. And again, if you look at the percentages, most of your muscles at rest, use glucose quite a bit of lactate. But when you're exercising, you're getting 80% of your muscle energy comes from lactate. So lactate, as you can see is a really important fuel. In fact, just to prove this to you, if you look at um again, this is done experimentally and the response of exercising muscles to catacholamines and how that's related to lactate if you see how, how much of your maximum oxygen consumption. So your V 02 max, so whatever your V 02 max is, we'll take a percentage of that. So you're basically exercising, you know, light exercise all the way to the severe ist exercise that you can perform, that's individualized. So that's your adrenaline concentration. And as you increase your, um, your output, the uh severity of your exercise, if you like, you're going to get an increase in adrenaline. And guess what if you look at your lactate concentration you get exactly mirroring the increase in lactate. So the more the harder you exercise, the more adrenaline you produce and the more lactate you produce. And we saw earlier why that happens, it's to get the production of ATP, uh lactate produces it very quickly. It's a very fast, fast producer of ATP. That's not because you're lacking ox street, uh liver and kidney, we said was using the quarry cycle to convert lactate to glucose. And that glucose. Now, as you saw a second ago, can be used in those organs that required glucose, uh like the brain and the immune system and most of it's from the liver. So, um, here's a common clinical conundrum, a case that I used to see all the time in I T U and then he might not. So, not just junior colleagues, by the way would fall into I think a misunderstanding. So this is the kind of case we had. This is again, true story, 68 year old male previously healthy, aside from a little bit of hypertension that was treated, he's admitted to the intensive care unit in septic shock with a pneumococcal pneumonia. His oxygenation is poor BP is low, heart rates fast, create any uh is poor, was high. So it's zero outputs pour. So he's got renal impairment, but he's not quite yet needing hemodialysis. So we're on our way maybe but not yet. He's got poor peripheral profusion with cold modeled skin, we intubated and ventilate them and we treat him with fluids and nor adrenaline with some effects. Things are getting a little bit better, but his lactate is persistently high. And, um, and uh this is kind of, we said earlier that high lactate signifies a poor prognosis. So the junior doctors and they weren't. So junior actually decide to hemodialyzer to get the lactate off. What do you think of that? Is that a good idea? I sorry, would you, would you try and he moved to dialyze this man only to try and remove the lactate. Uh, no, that, that like it would be used afterwards. Okay. Well, it's, I think you got the right answer. It's, it's, it's common, very common for people, you know, many even senior doctors to see that lactate and say let's dialyze the lactaid off. Does that make sense? I don't think so. Why? Because is it effective for a start? Probably not if you look at how much blood is cleared of lactate. And don't forget, lactate would normally be cleared by your various organs, especially your liver and kidneys. That could be going to the court recycle producing glucose but also other organs that will use lactate directly for fuel. That's how much blood is cleared. Normally, that's your blood and my blood clearing 1000 400 mils of black tape per, per minute. That's hemodialysis. It's about 3%. So, hemodialysis is not a great way to get rid of lactate. But even if it was, it doesn't solve the problem that's causing the rise in right tape. That's the key lactate psa marker. It's not usually, usually, it's not the problem itself. It's a marker of something underlying a stress that's underlying. So maybe the man had an ongoing infection that wasn't being treated in uh correctly with the right antibiotics or maybe he had an abscess or maybe you had pancreatitis. All these things are saying basically, you're, you're basically, you're shooting the messenger and it's not just a messenger, it's a vital messenger. So it's no point getting rid of the messenger because you're not going to get, you're not going to solve the problem. And if you don't believe that this is an old study that was published in the New England Journal Medicine many years ago. And there was a molecule called DCA dichloroacetate which basically ramps up your, your, your production of pyruvate. Hence, um, uses that lactate. So it reduces, it's used to reduce lactic acid and it works. So if you look at um what happens to lactate? If you give placebo or D C A, you'll see that DCA works to lactate is dropping. So you are removing locked, it reduces, locked in the blood. Great. What about survival? No difference. So it's not lactate. That's the problem. Usually it's not because of lack of oxygen or the lactate. It's particularly bad for you quite the opposite. It's that it's a marker of other things going on. A stress that you have to deal with. It didn't influence mortalities with salt because it doesn't treat the cause of the race. Electing. That's the key. The cause. Another myth I wanted to talk about was lactic acidosis. Now, everybody talks about lactic acidosis and this may seem a bit a bit esoteric. But it's important we know today that there are misconceptions around lactic acidosis. We believed that Lactic produced would cause a lactic acidosis. An acidosis of metabolic acidosis. Is this true? Strictly speaking, no, the cause of the acidosis that's associated with lactate. And I underline the word associated is that you have A T P and it releases its energy by becoming A D P, it's hydrolysized and that hydrol Asus releases a hydrogen ion. And if for some reason, um your hydrolysis of ATP exceeds the ability of A P A T P to be produced, then you will get in the mitochondria, then you will get a rise hydrogen. Because when you produce a T P, you use hydrogen on it. So you break down your A T P, you release a hydrogen in when you reproduce ATP, you, you, you basically absorb that hydrogen. I and if for some reason, your hydrolysis is overwhelming your ability to produce a T P. That's when you get arised. A raised in hydrogen eyes. In fact, ironically producing lactate actually absorbs a hydrogen ion. So the too often may go together and it may give you the impression that they're ones causing the other. But in fact, it's an associate. So here's an important practical aspect. So you have someone who comes in, they're unwell and we're gonna resuscitate them and your, your aggressively assess it necessitating them and your lactate becomes uh low in lowers, but it's not normal yet. Do you continue aggressively assess assisting these people until the light it becomes normal? So I think we shouldn't aggressive, doing a aggressive. So, I mean, if someone's BP, because metabolically, the acidosis is, well, what I'm saying is that someone's BP is low and say it was, I don't know, 70 systolic and you get it up to 85 systolic. I won't stop there. I'm going to keep going until it becomes normal. What about lactate, lactate is very high? Say it was at eight and it comes down to four. Am I going to stop there or maybe keep on resuscitating to check for the? Well, let's look at this. The problem is you're not going to carry on aggressively resuscitating at least after the initial phase of six hours. Why? Because you have to understand something about the pharmaco kinetics or the kinetics of like tape. Now see our tea is capillary, refill time. It's one of several markers that one to use to assess um the adequacy of peripheral peripheral profusion. And it's quite a good technique and it's been shown in several studies to be quite a good technique to assess the adequacy of your peripheral perfume. Okay. So if you've got someone who comes in um hypertensive, their model, their cold peripherally and you start resuscitating them, you'll see your C R T, your capillary refill time, we'll drop relatively rapidly. So you've succeeded resuscitating their profusion. If at the same time, you were to look at the lactate, it looks down quickly just like the C R T, but it stays abnormally elevated and then it starts second phase where it's slower. So the first six hours, you want to get that lactaid down and you want to get your C R T to normal. But after six hours, you're gonna get a slower reduction of lactate compared to your flow indicators. So from 6 to 24 hours. Let's say you want to stop aggressively resuscitating somebody. If this is the big one, if the other flow of variables are normal, because we expect lactate to take a little bit of time to start coming down. Now, be careful what I'm saying is in the first six hours, you definitely want to see a drop in lactate and you'll see in a second what I mean by that. But if your flow monitor your flow parameters are normal and your lactate is not quite normal yet or keep on giving fluid and pumping in more LORazepam answers because that is going to be harmful yet. So, yes, be aggressive in the first six hours. But don't, don't forget that lactate has a bi phasic response, the early rapid reduction in a slower recovery. But you forget you have to have a rapid recovery of your flow parameters. That could be really refill time. So once your flow is normalized, don't case black tape. Now, does this clearance of lactate mean anything? Yeah, absolutely. The early lactate clearance is very important. And if you look at clearance, that's over 10% an hour, you'll see you have a much greater survival. Then if your clearance is less than 10% an hour. So in the first six hours, in the first six hours, you want to drop your lactate by something of the order of 10% an hour for the first six hours. And your flow parameters and once your flow parameters are okay, then there's no point in keep pouring in more fluid or giving more visa pressors or inotropes because your lactate normally will slow down in its clearance after six hours or so. Okay. So here um we're coming towards the end and here is um uh an interesting case that I learned a lot from. So I was involved in where I was asked to be a um a peer reviewer for the American Journal of Physiology. And someone sent me a case report and to review. And so here's what the case was. The 60 year old male who was admitted to the accident, emergency department, the abdominal distention, discomfort, very cachectic cold, clammy without a fever and the vital signs were normal. So BP, heart rate were normal and no signs, no obvious um gross signs of macro circulatory failure. The past medical history was chronic renal failure. The and only that the labs showed a high white cell count raised CRP. So inflamed, a raised crap mean a very, very raised uh lactate dehydrogenase know near and lactate was 7.4 with a ph of 7.3 on the CT. There was a sides diffuse peritonitis and a pelvic mask which at surgery turned out to be lymphoma. It was decided that this was a bee type lactic acidosis and I'll come onto that in a second. Hence a warbird effect. And with chemotherapy, the lactic acidosis decreased uh successfully. The patient was discharged. And what was home and well, a year later now that's fine. Everything was perfect with this. But don't forget this is for an article in a journal of physiology. And they asked me to review this and I had a problem with one thing. So what was the one thing I'll tell you in a second. But so what was the warbird effect in case you've never heard of this? Very interesting affected by an incredibly interesting uh scientist, Otto Warburg won the Nobel Prize for his discovery of the actions of respiratory enzymes. So all the enzymes you hear about the spirit E cycle and the Krebs cycle. Krebs was one of the colleagues of Warburg were discovered by Doctor Warburg and he discovered that tumor's can produce massive quantities, electing they're out of control their production of lactic. Now, why would they produce lactic because the tumor will get angiogenesis, cell migration, immune escape metastases and most importantly, self sufficient metabolism. All thanks to lactate. And so what one of the reasons you get to kick tic, you lose all that weight. And you can see when patients have, you know, have cancer is because basically the tumor cells are triggering the normal tissues to produce masses of lac tape, so they can fuel their own re production, enhanced metastasize. So, lactate is a very vital um component to cells. In this case, cancer cells and there's no control over it. So it's got Gla Tayts being used being hijacked by the cancer cells and you like and to aid their own growth and it's out of control. What's interesting about Otto Warburg, by the way, for those that are interested in history, he was nominated 47 times for the Nobel Prize and as I wrote, who demand. So what do I mean by the type A or type B? Lactic acidosis? And this is a classic uh definition or categorization. So type A is the person who has got Stella or hypoxia and this type B with non hypoxic. So again, I'm not saying that if you're, you can't be hypoxic, of course, you can. But most cases are not in the type A, you'll have someone who like shock, severe, very, very severe anemia, uh seizures. If you have someone who has a seizure and you take their blood settle, you'll see very high lactate often at least for a short period of time until they recover in their cells are recuperate, cardiac arrest, uh global hypoxia, carbon monoxide, it starves the cells of oxygen and even regional hyperperfusion. So for example, mesenteric ischemia and the non type is sepsis. And we said sepsis was mainly do not to sell your hypoxia, but probably due more to the fact that you've got a stress and you're producing a lot of catacholamines. Hence, you're producing a lot of lack tape. It's a survival mechanism because it's the really glycol. If it's uh I mean deficiency, that's an important one. If you have a lack of vitamin B one and you get what we call berry, berry or wet berry, berry or shoshone berry berry. Um You can get the same thing and various other components as you can see here. Welcome through them all. My problem with this paper was that I felt that the authors hadn't adequately or at least in detail excluded the fact that this person might have a type, a hypoxic uh lactic hyperlipoproteinemia. And what they could and should have done was not just rely on BP and heart rate, but there are other um other things you can do and I won't go into them today. We haven't got time but things there are various, for example, CO2 monitors or so to metabolic monitors. We can use something called the CO2 gap or P CO2 gap that was not used. And they, the editors agreed with me and they made them put them in and uh that paper was published, but just illustrated something's about lactic. So to recap everything we've talked about. So you have a raised lap take. Oh my God. Is that bad news? Yes. It's always bad news, but not necessarily for the reasons you think is it due to hypoxia could be? But very rarely most of the time, it's just a marker of stress and it's needed it's a vital response to that stress. So you got to treat the stress, whether it's an infection or, or an inflammation. Can you dialogues it off? It doesn't work. You got it because you're not treating the cause unless there are other reasons to dialyze you obviously and don't forget, don't race once you've necessitate someone and they're flows improved, you can stop pacing the lactaid because it will come down slowly. Make sure it does keep coming down. I'm not saying to leave it because you might want to, you might see it going back up again if the person gets a secondary infection, but don't aggressively case it if, if your flow is improved. And I think that's all I have to say. So if there any questions, I'd be delighted to try and answer them any questions. Oh, yes. You said that the once uh resuscitate it, the acidosis will clear itself. It is like the metabolic uh changes whenever than the body which uh like I had a lecture regarding metabolic balance is in the body. One is through respiration and one is the body metabolic evils compared which has to keep the balance, the acidosis and ankylosis in the body. So once we resuscitate, it's the body's metabolic way of uh making the acidosis and alkalosis in the perfect balance. Right? I think what we're saying is that when you're assisting someone who's severely ill, you want to keep an eye on the flow parameters. And I said one of them could be completely refilled. That's not the only one, but it's not about use if that becomes normal. And you want to make sure that's normal. You don't want to take your time over that. At the same time, we're talking about a six hour period or so. You want to make sure your lactate is coming down, coming down at a rate of about 10% an hour. But it's coming down. Now, if your flow parameters have have achieved what looks like a normal value, your BP looks okay. Everything is looking okay. But the only parameter that seems to be raised is still lactate but everything else looks normal. Don't fall into the trap. You have to aggressively carrying on, forcing the lactate to come down. It will come down over time because the the kinetics of lactate is a rapid descent when you remove the stress and then it takes its time to come back into equilibrium. So the problem is if you were to aggressively carrying on treating the lactate, even though everything else is normalized, you risk using more fluid excess fluid, more catacholamines, excess, catecholamine, all these things have negative effects if you use them excessively. That's all we're saying. So everything looks like it's okay. And the only thing that's an outlier is lactate we're talking about after the first six hours or so because there's the main thing you remember is the bi phasic biphasic production of lactate. That's all. If you know that, then you can explain why you're not aggressively treating the lactate. You want to keep an eye on it, make sure it still comes down but not as fast. That's all anything else. And I think it was your grown lecturing. Uh And once you said that you don't uh wolf and the, I think it was sent when by uh you don't want to accept saturation access so that the blood couldn't uh ability filling time. It's two, it's overcrowded and the blood doesn't, uh the gas exchange is lost. That's one of the reasons we don't over fill it or oversaturated. Uh I don't think the saturation is the right word, I think. Yeah, resisting. Yeah. The problem is that we often, if someone is initially admitted to the accident emergency department where I T U in the, you have to decide what phase you're in the early phase for later phase in the very, very early phase. Often you need fluids, you need nor adrenaline. We talked last time about the advantages of maybe mixing the two together, but you definitely need fluids in the early phase, but you don't want to overdo it because what happens is that once you keep on going and going and going, you end up filling the patient so much that you get a Dema and then a Dema is harmful because for lots of reasons we talked about uh one of the first elections. Uh So what I'm trying to say is to put a break on the aggressive resuscitation. Once you past that very first phase, once the first phase is over and everything looks like it's back to where you want it to be, except for the lactate, which still is coming down, but it's not quite as fast as everything else. You don't want to keep on pouring in fluid and giving more catacholamines. If everything else looks like it's come back to normal because lactate will take a little bit of time to come down. That's all I'm saying. Okay. Anything else? So anyway, to answer the question, lactate friend or foe. Um It's a friend. It's a, it's a vital. If you don't have lactate, you will die. Your, your body needs lactic. So it's not an enemy, but it may be the marker of you trying to protect yourself by producing more lactate. If you see what I mean, if you didn't produce lactate, you would. In fact, there was a very interesting study that I didn't go into, but they looked at people who were severely ill with all kinds of shock when it's cardiogenic shock or whether it's septic and those that were not able to respond by producing more lactate did worse than those that did produce a lot of lactate because it's a very important, not just a marker but important adaptive response to the stress of shock or uh infection or whatever. Okay. If there are no other questions, then I will wish you a good day.