see: [bear - lactic acidosis](bear://x-callback-url/open-note?id=26767500-6B57-4B78-BF10-BD57A72B853A-25060-000008F2D053289C) # measurement - collect specimen in fluoride tube if analysis from a gas sample is not performed within 45 minutes - levels decrease with time after sampling - ​lactate increases with time when other tubes are used due to production by blood cells, especially with leukocytosis - **venous gas samples give results approximately 20% higher** than venous samples in fluoride tubes - laboratory usually only measures L-lactate - ​D-lactate is produced in short bowel syndrome so may not be recognised by standard assays - however the anion gap may still be elevated ## venous lactate mild 2.0 -4.0 mmol/L - [[Blood gas#anion gap|anion gap]]​ normal in 80% severe 4-10 mmol/L - AG normal in 50% ​very severe > 10 mmol/L - 100% mortality # toxic causes - [[Toluene toxicity]] - [[Lead]] or [[Iron overdose]] - [[​Lithium Toxicity]] - [[Valproate]] - [[Cyanide]] -- severe lactic acidosis - [[toxic alcohols]] — look for *lactate gap* (VBG lactate high, serum normal) - [[Aspirin overdose]] - [[carbon monoxide]] - [[Metformin overdose]] - [[Calcium channel blocker overdose]] - [[Paracetamol overdose]] - salbutamol and other beta agonists # What happens when you have a NAGMA but ↑ lactate?? > ↑ bilirubin, [[hypoglycaemia|hypoglycemia]], ↓ albumin, ↑ lactate suggests *liver failure* - [[Blood gas#albumin correction|↓ albumin]] / liver failure can cause a falsely lowered [[Blood gas#anion gap]] - (suspected or confirmed low albumin), low AG, ↑ bilirubin, and ↑ lactate may indicate *liver failure* as cause - the low albumin will mask a HAGMA which you would expect with elevated lactate - *multiple myeloma* and [[​Lithium Toxicity]] are the other causes of HAGMA and LAGMA besides low albumin --- # Lactate deep dive > I vaguely remember writing this diatribe some time a bit more than 5 years ago, probably while home quarantining from COVID. Which is to say I'm not sure about a) the quality and b) the attribution of sources; skimming it there is likely some plagiarism as it has the look of an unfinished symphony of notes where I had intended to go back and revise it and never did. I recall on the primary Viva I had a question about lactate and listed about 10 esoteric causes without them moving me on before I realised I forgot to say sepsis... I can pretty much guarantee that you'll be able to find a better summary about lactate elsewhere, but figured I'd put it here for posterity ## Overview Lactate is the **conjugate base** of organic acid Lactic acid. Lactic acid is ten times more acidic than acetic acid. This higher acidity is the consequence of the intramolecular hydrogen bonding between the α-hydroxyl and the carboxylate group. pKA 3.86 (which is to say, dissociated at physiological pH). Lactate produced by anaerobic respiration of muscle is L-(+) lactic acid, also known as (S)-lactic acid (“sarcolactic” acid, from the Greek “sarx” for flesh). In animals, l-lactate is constantly produced from pyruvate via the enzyme LDH in a process of fermentation during normal metabolism. It does not increase in concentration until the rate of lactate production exceeds the rate of lactate removal. Lactic acid produced by fermentation of milk is often racemic, although certain species of bacteria produce solely (*R*)-lactic acid. Lactate is an endogenous non-toxic molecule and an energetic substrate of gluconeogenesis. Based upon the Stewart-Fencl physicochemical approach to acid-base modification, all strong acids such as lactic acid are completely dissociated at physiological pH in water. **Thus, protons are generated with a commensurate drop in pH depending on the level of excess production and decreased metabolic clearance of lactate.** The drop in intracellular pH causes membrane transporters to extrude lactate and hydrogen ions (H+) to maintain physiologic intracellular pH. The resulting accumulation of extracellular lactate and protons subsequently lowers the extracellular pH. **Thus, while any accumulation of lactate results in lactic acidosis, it is again, the combination of excessive accumulation with a diminished metabolic clearance which is by far the most serious.** ![[pyruvate-lactate equation.jpg]] Intracellularly, the ratio of lactate to pyruvate is maintained at 10 : 1. There is way more lactate than pyruvate. The lactate has a pKa of 4.0, and so at a physiological pH it is fully dissociated into the lactate conjugate base and a H+ ion. Thus, ==for every 1 mmol of lactate in the extracellular fluid, one may expect the bicarbonate to decrease by 1 mmol.== Lactic acid is normally produced in excess about 20 mmol/kg/day. metabolized via the liver and kidney. Some tissues use lactate as a substrate and oxidize it to CO2 and H2O, but only the liver and kidney have the necessary enzymes to utilize lactate for gluconeogensis. ## Biochemistry see: [lactate and Lactic acidosis](https://acutecaretesting.org/en/articles/lactate-and-lactic-acidosis) ### Glycolysis see [Avicenna glycolysis FQ](http://avicennamd.org/fqs/glycolysis_FQ.html) Recall that during glycolysis, glucose is oxidized into pyruvate, and NAD+ is reduced into high-energy NADH. Pyruvate is useful, because it is the common end for the oxidation of fats, sugars, and proteins. Under aerobic conditions, it can enter the mitochondrian and convert to Acetyl CoA, starting the TCA cycle, which generates energy-rich NADH and FADH2 to drive the proton-gradient of the electron transport chain. ![[54729278-655E-470D-81F4-08ACA6110AC7.png]] **In anaerobic conditions, everything backs up**; as there is no oxygen to accept electrons in the electron transport chain, protons back up, and NADH (the product of the TCA cycle) builds up. Therefore, acetyl-CoA builds up, and pyruvate goes unused. As a result of THIS, there is less of a chemical gradient for pyruvate to enter the mitochondrial matrix, and it builds up in the cytosol. This also happens in exercising skeletal muscle, where NADH production exceeds the oxidative capacity of the respiratory chain. This results in in an elevated NADH/NAD+ ratio, favoring the reduction of pyruvate into lactate. Recall that in glycolysis, NAD+ is a coenzyme for the generation of ATP, and NADH builds up. If pyruvate builds up during anaerobic metabolism and NAD+ is not re-generated, glycolysis and ATP production will cease. Reducing pyruvate into lactate allows the oxidation of NAD+ and allows the process of glycolysis to continue progressing forward. ![[ECF83E19-D01F-49C3-B76B-F4D6E5A1CCF7.png]] The formation of lactate is the major fate for pyruvate in lens and cornea of the eye, kidney medulla, testes, leukocytes and red blood cells, because these are all poorly vascularized and/or lack mitochondria. It is released by these tissues into the blood, where it is taken up by the liver and converted into glucose via the cori cycle. **more on this later!** ![[4DA57642-949B-4C94-8FE0-E0A007CFA90F.png]] ### Lactate formation Lactate**, the anion that results from dissociation of lactic acid, is a product of glucose metabolism; specifically it is the end product of anaerobic **glycolysis**. The final step of anaerobic glycolysis is conversion of pyruvate to lactate by the enzyme **lactate dehydrogenase**. This last reaction provides a source of NAD+ essential for anaerobic glycolysis to proceed. Production of lactate is **the only means for glucose utilization and ATP production in erythrocytes** (which have no mitochondrion) and in exercising muscle cells (which have an oxygen debt). In well-oxygenated tissue cells that contain mitochondrion, pyruvate is not preferentially converted to lactate but rather metabolized to CO2 and H2O in mitochondria via two integrated metabolic pathways: the citric acid cycle and oxidative phosphorylation. Conversion of a molecule of glucose to lactate (anaerobic glycolysis) yields just two molecules of ATP, whereas conversion to carbon dioxide and water (aerobic glycolysis) has a much higher energy yield of 38 ATP molecules. ![[7elmoEU4wyGQcXRu48jQ7F8TXXEfzu2Iu9ASmWvnXNDnmlJdPCDLc0m0byv2plN0y2O0UB5ednBGS6UklbgDbMNc0MGOIWbZJgJnO_lfSauhXZbcXxYqR6dHK4oHtDD7IXYgDSxM.png]] ## Formation of Lactic acid Under anaerobic conditions, the major portion of the pyruvic acid is converted into lactic acid, which diffuses readily out of the cells into the extracellular fluids and even into the intracellular fluids of other less active cells. Therefore, lactic acid represents a type of “sinkhole” into which the glycolytic end products can disappear, thus allowing glycolysis to proceed far longer than would otherwise be possible. Indeed, glycolysis could proceed for only a few seconds without this conversion. Instead, it can proceed for several minutes, supplying the body with considerable extra quantities of ATP, even in the absence of respiratory oxygen. The **law of mass action** states that as the end products of a chemical reaction build up in a reacting medium, the rate of the reaction decreases, approaching zero. The two end products of the glycolytic reactions, (1) pyruvic acid and (2) hydrogen atoms combined with NAD+ to form NADH and H+. The buildup of either or both of these would stop the glycolytic process and prevent further formation of ATP. When their quantities begin to be excessive, these two end products react with each other to form lactic acid, in accordance with the following equation: ![[860A3710-9989-47A1-A250-DF4BA6731585.png]] Keep in mind that Lactate (the conjugate base of lactic acid) is a proton acceptor. Although it is mostly dissociated at physiological pH, this doesn’t change the idea that in principle, lactate itself reduces the accumulation of hydrogen ions. Part of why H+ ions accumulate in the first place is because the **hydrolysis of ATP produces a proton.** ![[3AF24630-EDFA-48B4-9696-82642E1F644F.png]] In other words, in anaerobic metabolism, the **cost** of energy production is acidosis, but lactic acid per se is not the cause of it. The inorganic phosphate removed from ATP is generally expected to buffer the “free proton” generated by ATP hydrolysis, and it is then incorporated int aerobic metabolism to produce more ATP. during normal metabolism, around 150 moles of H+ ions are recycled in this manner over 24 hours (Kreb, 1975). However, as the phosphate ion is rapidly recycled to produce more ATP (particularly in “stressed’ metabolically active tissues), this buffering ad recycling does not occur. The net production of ATP (i.e. *consumption of H+*)lags behind the anaerobic production of H+. Unbuffered intracellular protons leave the cell via the sarcolemmal Na+/H+ exchangers and reduce the pH of the blood gas sample. In summary, tissues which have a high rate of ATP turnover are going to generate an acidosis. Lactate production occurs by processes which are usually associated with increased ATP turnover, and may therefore be proportional to the acidosis, but it is not causally linked to it (so Robergs et al argue). ([Biochemistry of exercise-induced metabolic acidosis](https://journals.physiology.org/doi/pdf/10.1152/ajpregu.00114.2004) Robergs 1978). However, Lactate can also increase in the absence of increased ATP hydrolysis.** States which are known to cause severe metabolic acidosis and hyperlactataemia aren’t always associated with any sort of change in ATP hydrolysis. May 2012, in studying septic sheep using MRI, did not see any evidence that during severe sepsis, ATP hydrolysis increases. The sheep were injected with E coli and became septic, with MAP declining by 40 mmHg. The authors measured ATP:Pi, but not lactate. Other researchers have found that rises in lactate were not associated with any cellular metabolic evidence of tissue bioenergetic failure. Is hyperlactataemia in septic shocke more related to the inhibitory effects of cytokines and endotoxin on pyruvate dehydrogenase activity? **Increased lactate can occur in the absence of significant acidosis** Eg. salbutamol increases lactate with little effect on pH or bicarbonate. dialyzing patients with lactate-buffered solutions will raise serium lactate with little effect on pH and bicarbonate. **biochemically, lactate molecules should always produce acidosis** From the viewpoint of a quantitative approach to metabolic acidosis, lactate in solution should always decrease pH. Lactate is a strong anion with a pKA of ~4.0, full dissociated under normal physiologic conditions. By decreasing the strong ion difference, increasing lactate concentration should push the PCO2/pH buffer relationship in the direction of metabolic acidosis. This should happen no matter what the origin of the lactate. According to this theoretical framework, when a high lactate level is seen in the absence of acidaemia, a concurrent process just also be present which protects the pH. ### Role of pyruvate and metabolism to the Cori Cycle lthough lactate can be produced in all tissues, skeletal muscle, erythrocytes, brain and renal medulla tissues are the principal production sites in health. Normal daily lactate production is of the order of 1500 mmol. There are two main routes of lactate disposal: **conversion back into pyruvate** or elimination in urine. Although lactate is freely filtered at the glomerulus, it is almost all reabsorbed and normally **<2 % of lactate is removed from the body in urine**. The principal route of disposal begins with cytosolic conversion to pyruvate by the enzyme **lactate dehydrogenase**. (Worth noting here that because RBCs have no mitochondria, they have abundant LDH; when they are haemolysed, LDH increases; this is why LDH can be a surrogate marker of hemolysis). **Pyruvate** production as a result of glycolysis gets shunted into two main metabolic pathways: 1. Under **aerobic** conditions, it enters the TCA cycle after being oxidized into **acetyl-CoA** by pyruvate dehydrogenase, and a series of reactions occur to form ATP and NADH, which goes on to the process of oxidate phosphorylation which produces the majority of ATP in a cell. This produces CO2 and H2O. 2. Under **anaerobic** conditions, pyruvate generated from glycolysis enters into the **Cori cycle** (AKA **lactic acid cycle**). This leads to the **conversion to glucose** via **gluconeogenesis**. Oxidation of pyruvate via the citric acid cycle can potentially occur in all cells with mitochondrion, but gluconeogenesis is confined to liver and kidney cortex cells. ![[lactate-2.jpg]] ![[A36A4C44-62A6-4DEE-B8B0-4F6E63F210B8.png]] ## The fate of Lactate As mentioned earlier, the liver and kidneys are the most significant organs for lactate elimination, the liver accounting for disposal of around 60 % of circulating lactate and the kidneys for disposal of 25-30 %. **Overall, the body has immense capacity for lactate disposal**, which can, if necessary (e.g. following extreme exercise), rise **as high as 500 mmol/hour**, considerably higher than the basal rate of production. ### Cori/lactic acid cycle In the lactic acid cycle, pyruvate is converted to lactate, and NAD+ is regenerated from NADH. Subsequently, the NAD+ gets utilized in glycolysis to generate two molecules of ATP per molecule of glucose. Excess lactate gets shunted to the liver to undergo gluconeogenesis. **Cori cycle:** In muscle, blood cells, bone marrow, renal medulla, peripheral nerves, hypoxic tissue (glycolysis-dependent tissues) ![[4F35F8FF-1EC9-4E10-B260-E1D86F3495F1.png]] Hydrogen ions are produced in ATP hydrolysis to ADP. If O2 present, utilised by mitochondria for **oxidative phosphorylation**. If not, then ox/redux cannot happen, and H+ accumulates. ![[PBntZT-vJ1ZZyHOQEk9fy3zwTBvV6vlJH1bJqYT_0DR31QTF1T8gStaYawdwzs5xLZbaaJBEzFpiRYggGcpG3UJmXRXCyT73teUXUQpPZXfkIyQt9fwkoSMeb4DG3w3NgrEosmet.png]] ![[5140A770-457D-44A9-9A1F-D63FC0EF582F.png]] ![[17BD2A45-B64C-4EFC-942E-DDCD546BDEB3.png]] ## Normal blood lactate concentration Lactate produced within erythrocytes cannot be metabolized further (since no mitochondria) and is released to the circulation. In some tissues (e.g. skeletal muscle) lactate may be produced at a faster rate than it can be metabolized and in these circumstances lactate would also be released to circulation. In health, blood lactate concentration is maintained within the approximate range of 0.5-1.5 mmol/L. This reflects a balance between the rate of lactate release to blood from erythrocytes and other tissue cells and rate of lactate clearance from blood, principally by the liver and kidney. Exercise represents a physiological process in which this balance is temporarily upset due to the rapid increase in lactate production by muscle cells in temporary oxygen debt. In severe exercise, **blood lactate may rise to levels in excess of 20 mmol/L** but due to the capacity for rapid lactate disposal, in health this rise is only transitory. [Blood Lactate Measurements and Analysis during Exercise: A Guide for Clinicians](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2769631) ## Causes of acidosis in hyperlactatemia [Causes of acidosis in hyperlactataemia | Deranged Physiology](https://derangedphysiology.com/main/cicm-primary-exam/required-reading/acid-base-physiology/acid-base-disturbances/Chapter%20803/causes-acidosis-hyperlactataemia) [Lactate and lactic acidosis](https://acutecaretesting.org/en/articles/lactate-and-lactic-acidosis) Earlier we discussed the cause of lactic acid build up as a means to fight the build up of pyruvate from stopping glycolysis. Of note, the above describes the development of lactic acid; it doesn’t completely explain acidosis. The accumulation of H+ ions from **ATP hydrolysis to ADP** may be another component of the resultant acidosis observed during hyperlactatemia. In the presence of oxygen, hydrogen ions produced during ATP hydrolysis are utilized in the mitochondrial process of oxidative phosphorylation, but this is often not possible in the context of anaerobic glycolysis associated with hyperlactate production. Instead, hydrogen ions accumulate in blood, eventually overwhelming the bicarbonate and other buffering systems that maintain blood pH within normal limits (7.35-7.45). **The combination of hyperlactatemia and acidosis is called lactic acidosis** and although there is no universal agreement for definition of lactic acidosis, the most widely used is blood lactate >5.0 mmol/L in combination with pH <7.35 From a biochemical viewpoint the central problem is usually decreased utilization of pyruvate in oxidative or gluconeogenic pathways. Under these circumstances pyruvate can only be converted to lactate. For example, since oxygen is essential for pyruvate oxidation, any condition that deprives tissues of oxygen can lead to increased production of lactate, which then accumulates in blood at a faster rate than it can be removed by liver and kidneys. The problem is compounded by acidosis because the capacity of the liver to remove lactate from the circulation is pH dependent and severely impaired by reduced blood pH. In fact, experimental evidence suggests that at blood pH of 7.0 or less, lactate uptake is so impaired that the liver produces more lactate than it consumes \[9]. There is some renal compensation because acidosis enhances kidney uptake of lactate \[5]. However, this can only compensate for around 50 % of the hepatic loss and acidosis, whatever its cause, can be a major contributory factor in the pathogenesis of hyperlactatemia. From https://www.eddyjoemd.com/2020/01/how-does-lacate-turn-into-lactic-acid.html : In the cytosol, pyruvate turns into lactate (rather than move towards acetyl-CoA) for a number of reasons, again that I’m not going to get into, via lactate dehydrogenase. That lactate (via shuttles) gets to the cytosol of the liver and kidneys where it eventually makes its way into the Cori/Lactic Acid Cycle. The Cori cycle eventually spits out glucose. So far so good, right? Glucose via glycolysis seems to be metabolized into lactate, ATP, and water. Said ATP gets hydrolyzed into ADP and inorganic phosphate which releases that very necessary proton (H+). When conditions get revved up, i.e. septic shock, and an excess of lactate is being produced, then the cell cannot handle the metabolism of lactate and guess what’s also being overproduced? Said H+ which tags onto the lactate creating lactic acid. ## Types of Lactic Acidosis Cohen & Wood classification: Type A and B ### Type A: Hypoperfusion and hypoxia When an oxygen consumption/delivery mismatch occurs, with resulting anaerobic glycolysis. Examples of type-A lactic acidosis include all shock states (septic, cardiogenic, hypovolemic, obstructive), regional ischemia (limb, mesenteric), seizures/convulsions, and severe cases of shivering. * anaerobic muscular activity (sprinting, generalised convulsions) * tissue hypoperfusion (shock, cardiac arrest, regional hypoperfusion -> mesenteric ischaemia) * reduced tissue oxygen delivery (hypoxaemia, anaemia) or utilisation (CO poisoning) ### Type B: No hypoperfusion or hypoxia Still has inability of mitochondria to process the amount of pyruvate with which it is presented. Thus alternative metabolic pathways for pyruvate, as described in the lactic acid cycle, become activated which results in excessive levels of lactate. Examples of type-B lactic acidosis are liver disease, malignancy, medications (metformin, epinephrine), total parenteral nutrition, HIV, thiamine deficiency, mitochondrial myopathy, congenital lactic acidosis, trauma, excessive exercise, diabetic ketoacidosis, and ethanol intoxication. * B1: associated with underlying diseases * LUKE: leukaemia, lymphoma * TIPS: thiamine deficiency, infection, pancreatitis, short bowel syndrome * FAILURES: hepatic, renal, diabetic failures * B2: associated with drugs & toxins * phenformin * cyanide * beta-agonists * methanol * adrenaline * salicylates * nitroprusside infusion * ethanol intoxication in chronic alcoholics * anti-retroviral drugs * paracetamol * salbutamol * biguanides * fructose * sorbitol * xylitol * isoniazid * lactate-based dialysate in RRT * congenital forms of lactic acidosis with various enzyme defects — e.g. pyruvate carboxylase deficiency, glucose-6-phosphatase and fructose-1,6-bisphosphatase deficiencies, oxidative phosphorylation enzyme defects) * B3: associated with inborn errors of metabolism ***Causes in sepsis*** * Endogenous catecholamine release and use of adrenaline as an inotrope * Circulatory failure due to hypoxia and hypotension * Cytopathic hypoxia – widespread microvascular shunting and mitochondrial failure * Inhibition of pyruvate dehydrogenase (PDH) by endotoxin * Coexistent liver disease ## Conditions associated with elevated lactate - [[Mesenteric ischaemia]] (see also [here](https://www.hindawi.com/journals/bmri/2017/8038796/)) - salbutamol - Produces hyperadernergic state —> enhances glycogenolysis and gluconeogenesis —> more pyruvate production —> more lactate - EtOH - Metabolism of ethanol is associated with increased NADH/NAD+ ratio favoring conversion of pyruvate to lactate \[2]. Gluconeogenesis is also inhibited so that the combination of moderate hyperlactatemia and hypoglycemia is a not infrequent finding in patients suffering acute effects of alcohol abuse. - Pre-existing alcoholic liver disease exacerbates the acute hyperlactatemia-precipitating Type B lactic acidosis. - Alcoholics are deficient in thiamine, which is important to: * Bind magnesium * Move glycolysis and TCA cycle forward * Generate NADPH needed to make nucleotides, glutathione reactions, and metabolise pentode sugars * Alcoholics get IV thiamine 100mg prior to glucose (oral not sufficient) because giving sugar will cause intermediates of metabolism to back up, and worsen lactic acidosis. If pyruvate builds up during anaerobic metabolism and NAD+ is not re-generated, glycolysis and ATP production will cease. Reducing pyruvate into lactate allows the oxidation of NAD+ and allows the process of glycolysis to continue progressing forward. * See: [Thiamine for alcoholics](https://www.ebmconsult.com/articles/thiamine-administration-before-iv-glucose-alcoholics) and [[Alcohol-related disease]] and [[Alcohol Withdrawal Syndrome]] * [[Aspirin overdose]] * Salicylate overdose can be associated with lactic acidosis due to the inhibitory effect that salicylate has on oxidative phosphorylation. * [[Cyanide]] poisoning * A similar mitochondrial effect accounts for the lactic acidosis that occurs in cyanide poisoning. * anti-retrovirals * Most HIV patients prescribed anti-retroviral drugs develop mild chronic hyperlactatemia (serum lactate 1.5-3.5 mmol/L) , and in a small unpredictable minority this evolves to severe lactic acidosis. * [[Metformin overdose]] * Metformin impairs pyrvoate carboxylase in gluconeogenesis. By lechatlier’s principle, drives increase in pyruvate, dirving up lactate. However extent of this actually causing acidosis debatabe * [[Sepsis]] * The notion that lactic acidosis occurring in the context of critical illness is Type A and therefore always indicates tissue hypoxia is clearly over-simplistic. Critically ill patients are as likely as any other to be suffering Type B lactic acidosis and due consideration must be given to the causes of Type B lactic acidosis outlined above when assessing any patient (including those who are critically ill) presenting with raised blood lactate. * Sepsis is an additional and far more significant complicating issue that warrants special attention, not least because it is such a common feature of critical illness. Sepsis is a condition in which the distinction between Type A and Type B lactic acidosis is inappropriate because in some patients with sepsis, lactate accumulates despite adequate tissue oxygenation. * A number of mechanisms have been proposed for lactate accumulation in the absence of tissue hypoxia among patients with sepsis. These include reduced clearance of lactate from circulation by liver and kidneys; a specific defect induced by sepsis in the enzyme pyruvate dehydrogenase that impairs pyruvate utilization in the citric acid cycle; and increased pyruvate production. * Sepsis and septic shock are associated with a stress response that includes increased release of epinephrine (adrenalin). This hormone stimulates the membrane-bound enzyme Na+/K+-ATPase, which utilizes ATP generated by aerobic glycolysis to provide the energy necessary to “pump” ions into and out of cells. Na+/K+-ATPase stimulation increases aerobic glycolysis and thereby lactate production. * It has been hypothesized that the hyperlactatemia associated with sepsis may be at least in part the result of this epinephrine-stimulated aerobic glycolysis. * Whatever the mechanism it is clear that in many whose critical illness is either caused by or complicated by infection, lactic acidosis is not necessarily entirely the result of tissue hypoxia. In these circumstances measures taken to enhance tissue perfusion would be less effective in reducing blood lactate and resolving acidosis. * [[DKA]] * [[Paracetamol overdose]] * see [Understanding lactiic acidosis in paracetamol poisoning](https://pmc.ncbi.nlm.nih.gov/articles/PMC3018022/) ## Lactate in the heart In a normal heart, at rest, β-oxidation of fatty acids provides about 60%-90% of Adenosine triphosphosphate (ATP) while pyruvate produces 10%-40% of ATP. However, fatty acids show lower production efficiency and increased intracellular free fatty acids activate uncoupling proteins, so that protones leak into the mitocondria without generating ATP. That is why inhibition of β-oxidation is associated to an increased in mechanical efficiency of the left ventricle. **Lactate is an important fuel for the stressed heart.** During exercise the uptake of lactate by the myocardium and its use increase as well as during β-adrenergic stimulation and shock. In presence of increased lactate concentrations, lactate might represent up to 60% of cardiac oxidative substrate. During shock, lactate is the most important fuel for the heart. Indeed, in laboratory animals, lactate depletion is associated with shock and mortality, while lactate infusion increased cardiac performance in cariogenic and septic shock. Hyperlactatemia can be viewed as part of the stress response including increased metabolic rate, sympathetic nervous system activation, accelerated glycolysis and a modified bioenergetic supply. In animals with cardiogenic shock and in patients with cardiogenic shock, a marked increment in glycolysis and gluconeogenesis associated with hyperlactatemia was described. In healthy subjects in in cariogenic shock, it was observed, using an infusion of labelled lactate, that 50% of this lactate was oxidized and 20% used for glucose synthesis, without differences between the two subgroups. All these data strongly suggest that lactate is a source of energy in stress conditions. #### Cardiac energy metabolism https://heart-bmj-com.ezproxy.library.uq.edu.au/content/96/11/824 ![[69719B1F-3B9E-4C58-B576-114BF2AD95AD.png|Illustration of the flow and regulation of substrates through the oxidation of glucose and β-oxidation of fatty acids]] ### Significance of Lactate in ACS Few investigations assessed whether lactate values are a diagnostic tool in patients with chest pain. In 129 patients with chest pain, lactate values measured on arrival identified those chest pain patients with critical cardiac illness (*i.e*., severe congestive heart failure) while lactate concentrations within the normal range had a high negative predictive value for diagnosis of acute myocardial infarction (AMI). In patients arriving at the emergency department for suspected AMI, lactate values on arrival were highly sensitive for the diagnosis of AMI, mainly in those patients with more than 2 h of chest pain. In 229 patients admitted to coronary care unit admission lactate showed the greatest predictive power for shock development. ***Lactate AMI study:*** [Diagnostic Performance of Venous Lactate on Arrival at the Emergency Department for Myocardial Infarction - Gatien - 2005 - Academic Emergency Medicine - Wiley Online Library](https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1553-2712.2005.tb00844.x?sid=nlm%3Apubmed) **Methods:** A prospective, double‐blind observational study was done in a tertiary care ED. From January to April 2000, all consecutive patients presenting with chest pain were eligible. Lactate level was obtained on arrival and compared with two criterion standards for the diagnosis of AMI: the World Health Organization (WHO) and the Joint European Society of Cardiology/American College of Cardiology Committee (ESC/ACC) classifications. A lactate level greater than 1.50 mmol/L was considered positive. **Results:** Between January and April 2000, 718 patients were enrolled. By the WHO criteria, **64 patients suffered an AMI**, **of whom 59 had an elevated lactate level**, yielding a **sensitivity of 92%** (95% CI = 86% to 99%), a specificity of 44% (95% CI = 40% to 48%), and a **negative predictive value (NPV) of 98%** (95% CI = 97% to 99%). **For all patients presenting with more than two hours of chest pain (/n/=34), the lactate level was elevated.** When using the ESC/ACC criteria, 100 patients sustained an AMI, of whom 88 had an elevated lactate level, yielding a sensitivity of 88% (95% CI = 82% to 94%), a specificity of 46% (95% CI = 42% to 50%), and an NPV of 96% (95% CI = 94% to 98%). The sensitivity of the first ECG to diagnose AMI is shown in Figure 6 (second image below). Of the 64 patients with AMI by WHO criteria, 45 (71%) had a diagnostic ECG at point of care. Of the 19 patients with a normal or non-diagnostic ECG, 17 had elevated lactate levels, indicating that the lactate level added to the diagnostic ability of the ECG at the point of presentation. ![[D55A3B82-B804-4E46-96B2-5CD5D28B8809.png]] ![[8F660FB0-3D79-47EC-8795-E30643DC1B61.png]] **Conclusions** Venous lactate level at presentation is highly sensitive for the diagnosis of AMI, particularly in patients with more than two hours of chest pain. Given its limitations in specificity and ability to detect creatine kinase‐MB‐negative/troponin‐positive microinfarcts, further research is needed to determine how lactate can complement other cardiac enzymes in risk‐stratifying all acute coronary syndromes. ## A. Lactate Myths/controversies (as per Paul Malik, et al) * [The origins of the Lacto-Bolo reflex: the mythology of lactate in sepsis - Spiegel - Journal of Thoracic Disease](http://jtd.amegroups.com/article/view/34647/html) * [iSepsis - The Lactate Myths](https://emcrit.org/isepsis/isepsis-lactate-myths/) Paul Marik * [Understanding lactate in sepsis & Using it to our advantage](https://emcrit.org/pulmcrit/understanding-lactate-in-sepsis-using-it-to-our-advantage/)EM crit Discovered in sour milk by a Swedish apothecary assistant, Karl Wilhelm Scheele, in 1780, lactic acid first achieved prominence as a prognostic aide in the initial 1992 ACCP/SCCM definition of sepsis (Bone *et al*). Since then its role in septic shock has only expanded and become more entrenched. Recent studies (Andromeda-shock) suggest possible harms from lactate-guided sepsis resuscitation approach. Surviving Sepsis campaign has continued to reinforce the idea that lactate should be interpreted as tissue hypo-perfusion: * 1992 — lactate is a marker of end-organ dysfunction per ACCP/SCCM definition of sepsis * 2004 — surviving sepsis campaign published the first iteration of their sepsis guidelines reasserting that elevations in serum lactate levels should be considered a marker of tissue hypoperfusion. * 2004-2015 — Over the ensuing years lactate’s place in sepsis resuscitation only grew more ensconced as subsequent iterations of SSC treatment guidelines began to link its elevation to the administration of intravenous (IV) fluids. * 2015 — SSC’s recommendations were given regulatory support when the Center of Medicare and Medicaid Services (CMS) announced the initiation of their own **quality measure, the SEP-1 criteria**. This document essentially mandated hospitals to track clinicians’ performance of completion of treatment bundles at 3 and 6 hours. Similar to the SSC’s bundles, lactate was featured heavily as marker to guide fluid resuscitation, only now tying **compliance with such a strategy to the threat of financial compensation.** * 2017-2018 — Subsequent versions of the SSC conceded that all elevations in serum lactate are not necessarily due to end-organ dysfunction and hypoperfusion * 2019 — Andromeda SHOCK trial: ### 1. Elevated lactate in septic shock is not due to anaerobic metabolism The concept of lactate as a marker of end-organ hypoperfusion, or a surrogate for anaerobic metabolism at a cellular level is deeply rooted in the critical care literature. Much of this originates from research examining lactate production in exercising muscle. While multiple models of shock have demonstrated an association between lactate and tissue hypoxia, in sepsis this is rarely the case, where blood flow to the organs is often increased and partial pressure of oxygen (PO2) at the level of the tissue is normal or even high. In fact, elevations in lactate can and often occurs even in the setting of increased blood flow, with no clear association between oxygen delivery and serum lactate values. This was most recently demonstrated in a reanalysis of the Albumin Italian Outcome in Sepsis (ALBIOS) Study, in which they found that up to lactates of 5.6 mmol/L were independent of oxygenation. ### 2. Elevated lactate in septic shock is mostly due to stimulation of beta-2 adrenergic receptors Lactate is derived from pyruvate by lactate dehydrogenase (LDH). Lactate and pyruvate are maintained at an equilibrium of roughly 10:1. In sepsis this ratio shifts to favor lactate. Catecholamine stimulation, via the beta 2 pathway is associated with increased **pyruvate**, and therefore by Le Chatelier’s principle, leading to an increased lactate. When patients are administered epinephrine to combat sepsis-related shock, increases in serum lactate levels are observed. In the setting of septic shock, not only is there catecholamine increased aerobic glycolysis but pyruvate dehydrogenase (the enzyme responsible for shifting pyruvate into Krebs cycle metabolites) is dysfunctional, so more pyruvate is shifted to lactate. A similar phenomena is seen in patients receiving albuterol for asthma exacerbation, and epinephrine in septic shock. The causative role of these pathways in producing hyperlactatemia is illustrated in studies where investigators inhibit their progression, leading to decreases in lactate production. Esmolol infusions, to blunt the catecholamine pathways of septic shock cause falls in serum lactate levels alongside a decrease in oxygen delivery, reinforcing the concept that a large portion of the hyperlactatemia observed in sepsis is due to an elevation in circulating catecholamines. Similarly, the use of dexmedetomidine has been observed to be associated with a significant decrease in circulating intrinsic catecholamines and serum lactate levels. While the lactate production might be in partly secondary to dysfunctional metabolism, it is not useless, it is an essential fuel for tissues undergoing stress. Taken together this suggests a complex picture of metabolic failure in sepsis that simply cannot be explained by tissue hypoperfusion and hypoxemia. In the setting of increased oxygenation, and catecholamine stimulation, pyruvate generation is increased. However, the pathway into the Krebs cycle is inhibited leading to greater lactate generation and an increase in the lactate to pyruvate ratio, and decreased adenosine triphosphate (ATP) (especially in non survivors). When viewed from this perspective, it is obvious that resuscitation strategies intended to improve oxygen delivery by augmenting cardiac output with aggressive fluid resuscitation are destined to fail. And trending serum lactate levels to assess the effectiveness of such strategies is nonsensical. ### 3. Elevated lactate in shock might be a beneficial compensatory response asdf ## B. Clinical applications 1. **Identification of occult shock: Lactate still works.** pdf 2. **Serial lactate levels to monitor a patient in septic shock? Unknown utility.** asdf 3. **Lactated Ringer’s (LR): Still a physiologically sensible choice.** asdfsd [@eddyjoemd: an intensivist on a learning frenzy: Lactate in IVF Leads to Lactic Acidosis?](https://www.eddyjoemd.com/2020/01/lactate-in-ivf-leads-to-lactic-acidosis.html) [@eddyjoemd: an intensivist on a learning frenzy: How Does Lacate Turn Into Lactic Acid?](https://www.eddyjoemd.com/2020/01/how-does-lacate-turn-into-lactic-acid.html) 4. **Epinephrine in septic shock: Underutilized due to fear of lactate?** Pathologic lactic acidosis occurs with excessive production of lactate exceeding the livers capacity to metabolize it. Medications and toxins that cause lactic acidosis: Alcohols Acetaminophen HAART Beta-adrenergic agonists Biguanides (metformin) Cocaine Cyanogens Halothane Propofol Isoniazid Salicylates Valproic acid Sulfasalazine Usually, lactate produced by anaerobic glycolysis: LDH oxidises NADH to generate Lactate. The pyruvate either enters Krebs cycle as Acetyl CoA, or goes to liver to form gluconeogenesis Production of lactate is the only means for glucose utilization and ATP production in erythrocytes (which have no mitochondrion) and in exercising muscle cells (which have an oxygen debt). This is essential to generate the NAD+ needed for glycolysis to proceed again! Lactate gets eliminated in urine (60%), or goes to lever to go back to pyruvate under LDH for gluconeogensis. (Cori cycle) # Role in Medicine Measurement of blood lactate concentration has traditionally been used to monitor tissue oxygenation, a utility based on the wisdom gleaned over 50 years ago that cells deprived of adequate oxygen produce excessive quantities of lactate. The real-time monitoring of blood lactate concentration necessary in a critical care setting was only made possible by the development of electrode-based lactate biosensors around a decade ago. These biosensors are now incorporated into modern blood gas analyzers and other point-of-care analytical instruments, allowing lactate measurement by non-laboratory staff on a drop (100 µL) of blood within a minute or two. ## Lacto-bolo reflex - high lactate doesn't always mean the patient needs more fluids ## Sources: **Basics and Biochem** 1. https://www.ncbi.nlm.nih.gov/books/NBK470202/ Stat Pearls Lactic acidosis 2. [Lactate and lactic acidosis](https://acutecaretesting.org/en/articles/lactate-and-lactic-acidosis) Acute care testing (good article!) 3. [Metabolic origins and metabolic fate of lactate | Deranged Physiology](https://derangedphysiology.com/main/cicm-primary-exam/required-reading/acid-base-physiology/acid-base-disturbances/Chapter%20802/metabolic-origins-and-metabolic-fate-lactate) 4. [Causes of acidosis in hyperlactataemia | Deranged Physiology](https://derangedphysiology.com/main/cicm-primary-exam/required-reading/acid-base-physiology/acid-base-disturbances/Chapter%20803/causes-acidosis-hyperlactataemia) 5. [Metabolic fate of lactate, acetate, citrate and gluconate | Deranged Physiology](https://derangedphysiology.com/main/cicm-primary-exam/required-reading/body-fluids-and-electrolytes/manipulation-fluids-and-electrolytes/Chapter%20414/metabolic-fate-lactate-acetate-citrate-and-gluconate) **Marik lacto-bolo critique** 6. [iSepsis - The Lactate Myths](https://emcrit.org/isepsis/isepsis-lactate-myths/) Paul Marik 7. [The origins of the Lacto-Bolo reflex: the mythology of lactate in sepsis - Spiegel - Journal of Thoracic Disease](http://jtd.amegroups.com/article/view/34647/html) **ANDROMEDA-SHOCK** 8. [ANDROMEDA-SHOCK: Peripheral Perfusion vs Serum Lactate in Septic Shock - REBEL EM - Emergency Medicine Blog](https://rebelem.com/andromeda-shock-peripheral-perfusion-vs-serum-lactate-in-septic-shock/) 9. [Should We Stop Trending Lactate in Septic Shock? ANDROMEDA-SHOCK Published - PulmCCM](https://pulmccm.org/randomized-controlled-trials/should-we-stop-trending-lactate-in-septic-shock-andromeda-shock-published/) **?values of lactate clearance** 10. https://emcrit.org/wp-content/uploads/2013/06/Lactate-Kinetics.pdf “The value of blood lactate kinetics in critically ill patients: a systematic review” 2016 11. [Lactate clearance as a target of therapy in sepsis: A flawed paradigm.OA Critical Care](http://www.oapublishinglondon.com/article/431) **Special considerations** 12. [Metformin-induced lactic acidosis with emphasis on the anion gap](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4264704) 13. [The Phantom of Lactic Acidosis due to Metformin in Patients With Diabetes | Diabetes Care](https://care.diabetesjournals.org/content/27/7/1791) 14. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3962942/ Lactic acidosis in DKA 15. [Evidence for a detrimental effect of bicarbonate therapy in hypoxic lactic acidosis | Science](https://science.sciencemag.org/content/227/4688/754) 16. [Blood Lactate Measurements and Analysis during Exercise: A Guide for Clinicians](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2769631) 17. [Clinical significance of lactate in acute cardiac patients](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4549782/) 18. [Diagnostic Performance of Venous Lactate on Arrival at the Emergency Department for Myocardial Infarction - Gatien - 2005 - Academic Emergency Medicine - Wiley Online Library](https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1553-2712.2005.tb00844.x?sid=nlm%3Apubmed)”venous lactate sensitive for AMI” 19. https://heart-bmj-com.ezproxy.library.uq.edu.au/content/96/11/824 “Modification of myocardial substrate utilisation: a new therapeutic paradigm in cardiovascular disease”