Elevated Anion Gap Metabolic Acidosis (ABG Interpretation - Lesson 8)

[Applause] [Music] hello this is Eric strong from the Palo Alto VA and Stanford University this is the eighth lecture in this course on understanding ABG's and the topic is elevated anion gap metabolic acidosis while lectures two three through seven focused on providing a collection of rules for determining a patient's acid-base status lectures 8 through 12 will discuss the differential diagnosis for each of the five general paths of physiologic states of acid-base balance and provide some insight at how to establish a specific diagnosis in an individual patient this particular lecture is the longest of the course and will include a fair amount of biochemistry that may be intimidating please do not bother memorizing specific chemical structures or enzymatic pathways I will review these here because it helps to solidify your understanding of which medical conditions result in which acid based problems however knowledge of which hydroxyl group bonds to which carbon atom is not going to be important at the bedside the specific learning objectives of this lecture are to know the differential diagnosis of an elevated anion gap metabolic acidosis and to be able to identify the specific ideology of an elevated gap acidosis in individual patients for details on how the anion gap is measured and how to identify the presence of an elevated gap metabolic acidosis please review lecture 5 the differential diagnosis of an elevated gap acidosis is fairly long in order to remember them several mnemonics have entered into common usage in general I hate mnemonics but one for elevated gap acidosis is so prevalent that it requires mentioning this is the mud piles mnemonic I'll run through it briefly M is for methanol you for uremia D for diabetic ketoacidosis p for para aldehyde I is variably for inh iron intoxication infection or essentially whatever you want it to be for L is for lactic acidosis efore ethylene glycol or ethanol and s for salicylic acid so that's the differential diagnosis sort of there are a number of reasons that I don't like this demonic which I won't get into here in any detail but take my word for it that it's not very good so let's get rid of mud piles in 2008 several physicians in Lancet recommended a new elevated gap acidosis pneumonic Goldmark G is for glycols over Axio prolene l4 l lactate d 4d lactate m for methanol a for aspirin R for renal and K for ketoacidosis this is certainly an improvement another mnemonic that is used frequently possibly more so in emergency medicine than in internal medicine is Colt k4 ketoacidosis you for Urania l for lactic acidosis and T for toxins I personally really like this because it's short to the point and gives a more appropriate level of emphasis to the three most common diagnoses at this point I'm going to talk about each diagnosis on the differential in some detail as I said at the beginning there will be a fair amount of biochemistry this is not for you to memorize but rather to help you understand why certain diseases result in the specific types of elevator gap acidosis I'll start with the most important etiology lactic acidosis so where does lactate come from here is a basic schematic of the formation of lactate it starts with glucose which undergoes the multi-step process of glycolysis to form pyruvate along the way generating a few ATP and reducing nad to NADH under normal circumstances pyruvate is converted into acetyl co a with the help of thymine and some more nad acetyl co a can then enter the citric acid cycle also called the krebs cycle or TCA cycle where it converts chemical energy into something that can be used by the electron transport chain to generate many ATP in a process known as oxidative phosphorylation all of these steps here require the presence of oxygen and functioning mitochondria in some circumstances however pyruvate is redirected elsewhere for example in anaerobic conditions there is inadequate oxygen to allow the citric acid cycle and electron transport chain to function there are also places where mitochondria aren't found such as red blood cells and circumstances where mitochondria are not functional such as cyanide poisoning in these circumstances pyruvate is reduced into lactate with the catalytic assistance of lactate dehydrogenase this reaction oxidizes NADH back to nad which can then be recycled in the process of glycolysis that may be where lactate comes from on a biochemical scale but where does it come from and go to on a more an atomic scale anatomically speaking lactate commonly comes from three locations first as just mentioned red blood cells which lack mitochondria and therefore require the formation of lactate this is actually an interesting phenomenon since it means that RBC's are incapable of using the oxygen they are responsible for delivering it also means that a small amount of lactate in the blood is always present second whenever cells are either starved from oxygen or have mitochondria that for some reason aren't working properly they produce lactate finally in exercising skeletal muscle production of NADH exceeds the oxidative capacity of the electron transport chain the increased NADH to nad ratio kinetically favors reduction of pyruvate to lactate now once lactate is formed what happens to it most will travel to the liver where it will be reconverted back into pyruvate some pyruvate will then enter the citric acid cycle while some will enter the process of gluconeogenesis and be transformed back into glucose at which point it will re-enter the systemic circulation this is known as the Cori cycle an alternate fate of lactate is filtration in the kidneys and elimination in the urine this is usually only relevant once the blood lactate levels exceed a certain threshold commonly believed to be about five millimoles per liter at first this was believed to be the whole story however in recent decades we have begun to realize that there are a couple of additional potential sources of lactate first in some patients with bacterial overgrowth and high glucose delivery to the colon intra colonic bacteria can produce excessive amounts of lactate which can be absorbed to the gut wall this condition known as di lactic acidosis will be discussed in a minute in addition certain malignancies can produce lactate themselves for reasons which are not fully known the malignancies most commonly implicated in this are lymphoma leukemia and multiple myeloma there are a fair number of medications and toxins that have been associated with lactic acidosis the known mechanisms are too diverse to review in any detail in this lecture but they generally involve disruption of oxidative phosphorylation either by direct enzyme inhibition or by more general disruption of mitochondrial function I will discuss ethanol and the toxic alcohols later in this lecture and carbon monoxide will be discussed in lecture 19 which will be dedicated to the oxygen saturation gap the astute viewer might have noticed that there is one medication that is conspicuously absent from this list metformin metformin has long been attributed as the cause of many cases in the literature of lactic acidosis and I want to spend a couple minutes talking about it metformin is a biguanide which are a class of diabetes medications which work through an unknown mechanism to reduce gluconeogenesis by the liver they have long been thought to caused lactic acidosis as a side effect one that was most prominently seen in patients with chronic kidney failure heart failure and hepatic dysfunction this belief was probably the consequence of a superfood surely similar medication fen Foreman being linked to lactic acidosis and subsequently pulled from the market in 1977 however it has become clear with time that the concern over metformin seems largely if not solely based on the unjustified connection to fen Foreman along with anecdotes and isolated case reports in 2010 a Cochrane review was published that examined 347 separate studies of metformin each of which involved some form of monitoring for lactic acidosis these 347 studies included 70,000 490 patient years of metformin use many of these patients had conditions generally considered to be contraindications for metformin and one trial even explicitly included only patients with renal insufficiency the results not a single case of lactic acidosis was reported not one well there have been hundreds of individual case reports implying or asserting a patient developed lactic acidosis as a consequence of metformin use almost all of these patients had significant comorbid conditions that could provide alternative explanations as to the cause of the underlying acidosis the incidence of lactic acidosis among diabetics on metformin is likely identical to that among diabetics not on metformin this study is particularly convincing given its source is the Cochrane Collaboration for those of you not familiar with Cochrane reviews I'll just say that they have a strong history of published an independent high quality work that investigates the evidence for or against a particular intervention their default conclusion is usually that there is not enough evidence to argue for or against anything at all and that more research is needed before making a definitive statement therefore when the Cochrane authors writes quotes there is no evidence from prospective comparative trials or from observational cohort studies that metformin treatment increases the incidence of lactic acidosis compared with other anti hyperglycemic treatments I am convinced there certainly remains much skepticism in the medical community about this issue of particular concern is whether metformin can to lactic acidosis during an episode of acute kidney failure as well as whether it should be withheld for 48 hours before and after administration of IV contrast there is insufficient evidence available to comment currently on those two questions d lactic acidosis is a relatively unique form of lactic acidosis that occurs as a consequence of lactate having two enantiomers the Ellen antemer is the common form which is produced in humans primarily via the reduction of pyruvate by lactate dehydrogenase there also exists the mirror image of a lactate which is d lactate d lactate does not normally occur in the body but can be produced by colonic bacteria in patients who have undergone either jejunal ileal bypass or extensive resection of small bowel in these patients unusually high amounts of carbohydrates reach the colon where the bacteria there can metabolize it into D lactate which is then absorbed through the gut wall unfortunately lactate dehydrogenase normally responsible for catalyzing lactates oxygenation back into pyruvate within the liver does not recognize D lactate therefore D lactate accumulates as it is slowly eliminated via the kidneys or metabolized without the benefit of an enzyme catalyst many patients who have undergone significant resections of the small bowel have asymptomatic mild d lactic acidosis when symptoms occur they are largely nonspecific but always includes altered Mental Status with a consistent subjective observation that affected patients appear drunk the labs in an effective patient will reveal an elevated anion gap acidosis after eating that resolves with fasting since standard assays for measuring lactate actually utilize lactate dehydrogenase they are specific for L lactate thus these patients initially appear to have normal lactate levels a special assay that utilizes D lactate dehydrogenase exists but it is not readily available at most hospitals there's a popular system of classifying lactic acidosis known as the Coen woods classification which divides ideologies into type A and type B in type A there is evidence of tissue hypoperfusion such as that seen with shock profound hypoxia acute limb ischaemia or bowel infarction in type B there is no hypoperfusion type B has further been subdivided into B 1 which is lactic acidosis secondary to another medical disorder most commonly hepatic or renal failure or malignancy B 2 is lactic acidosis secondary to medications or toxins and B 3 is that secondary to inborn errors of metabolism I'm not personally a big fan of the system in that it doesn't really feel intuitive to me I prefer thinking about lactic acidosis like this there is usually a problem with increased production of lactate this could be because of problems with oxygen delivery as you would see in shock ischemic limb Balon fraction severe hypoxemia and carbon monoxide poisoning alternatively this could be because of problems with oxygen utilization as with hereditary enzymatic defects mitochondrial toxins or thiamine deficiency in rare circumstances lactate can be produced from tumors or produced on account of increased motor activity instead of increased production that could be a problem with decreased clearance as seen in hepatic or renal failure because the kidneys aren't a significant source of lactic clearance until lactate levels are already high it means that kidney failure in the absence of any other mechanism will not be sufficient to generate a lactic acidosis it will only make a lactic acidosis from another cause a bit worse finally lactate levels can be elevated due to GI absorption as seen in the-- lactic acidosis next I'll talk about ketoacidosis keto acids also known as ketone bodies our small compounds synthesized by the liver to be used as alternate fuel by cells during periods of relative glucose deficiency acidosis caused by the ketoacids is well described in three situations diabetes where the condition is usually known as diabetic ketoacidosis or DKA starvation and chronic alcoholism ketoacidosis for both diabetes in alcoholism is commonly found in conjunction with lactic acidosis as well as a mild metabolic alkalosis from vomiting both of which can complicate the ability to make a diagnosis to understand why these three situations produce keto acids as well as appreciate an important limitation of making this diagnosis I'll need to briefly review the formation of keto acids formation of keto acids requires lipolysis of triacylglycerols in adipose tissue this step is inhibited in the presence of insulin and stimulated by epinephrine growth hormone cortisol and glucagon the influence of regulatory hormones at this point is the reason why diabetics lacking insulin or in a state of physiologic stress can develop DKA also during fasting states insulin levels are low and glucagon high which would also drive this process the free fatty acids travel on the blood bound to albumin they can be taken up by most tissues and directly oxidized for energy in the liver however excess acetyl co a that is derived from beta oxidation of those fatty acids and not utilized in the citric acid cycle is diverted into the formation of acetyl acetate some acetyl acetate undergo spontaneous break down into acetone which is responsible for the fruity smell sometimes detected on the breath of patients with severe DKA acetoacetate can also be enzymatically reduced to beta hydroxy butyrate beta hydroxy butyrate is the predominant ketone form during states of ketoacidosis particularly in alcoholic ketoacidosis on account of an unusually high NADH to nad ratio unfortunately the standard nitroprusside assay which is used by most labs to detect the presence of ketone bodies only detects Osito Tate in acetone which explains why there is a relatively high false negative rate with urine and serum tests for ketones to reflect this type of uncertainty some labs have stopped routinely reporting the presence or absence of ketones in the urine and no longer report serum ketones as a titration threshold but rather as either present or absence beta-hydroxybutyrate can be measured directly but this is often a test that needs to be submitted to an outside lab and therefore the result does not come back within a clinically useful time frame as a quick point on terminology while there are three key to embodies only one of them is actually a keto acid acetone and acetyl acetate are both ketones but beta hydroxy butyrate is not while beta hydroxy butyrate and acetoacetate of both acids but acetone is not therefore the term keto acid only really appropriately applies to acetyl acetate even if common usage it refers to all three compounds in alcoholics there is an additional complicating biochemical pathway which is the breakdown of ethanol itself the first step in this process is the oxidation of ethanol to acetaldehyde which is catalyzed by the important enzyme called alcohol dehydrogenase this oxidation converts nad to NADH remember from the previous diagram that a relatively high NADH to nad ratio helps to drive conversion of acetyl acetate to beta hydroxy butyrate leading to high levels of the latter in alcoholics with ketoacidosis the next step in ethanol metabolism is conversion of acid aldehyde to acetate which is assisted by an enzyme called aldehyde dehydrogenase finally acetate is converted into acetyl co a at which point it can either enter the citric acid cycle and provide energy for the generation of ATP this is how earthen all can provide a major source of calories for alcoholics alternatively the acetyl co a can be used as a precursor for keto acids as we just saw there is an important connection here between ketoacidosis and lactic acidosis which increases the propensity for alcoholics to develop the latter diagnosis the connection concerns the possible fates of pyruvate pyruvate can either be oxidized to form acetyl co a which will either enter the citric acid cycle or be converted to keto acids alternatively pyruvate can be reduced to form lactate the former reaction requires nad and converts it to NADH while the latter reaction requires NADH and converts it to nad thus one of the major determinants about whether pyruvate enters the citric acid cycle or as diverted into the formation of lactic acid is the relative concentrations of nad and NADH as ethanol metabolism results in the production of NADH this helps to drive this balance more towards lactate than normal when you also consider that most alcoholics have some degree of hepatic dysfunction and that the liver is responsible for most of the clearance of lactates you will hopefully appreciate why the development of lactic acidosis in alcoholics is so common even in the absence of tissue hypoperfusion renal failure the elevated anion gap metabolic acidosis frequently seen in renal failure occurs for two reasons first there is a failure to excrete hydrogen ions in the kidney this is due to decreased excretion of ammonium ion and decreased excretion of titratable acids predominantly phosphoric acid the second reason is the accumulation of unmeasured anions these include phosphate sulfate your rates and hip your rate interestingly there is only partial overlap between the cause of the acidosis and the cause of the anion gap which helps to explain why patients with early renal failure may have only a non-gaap acidosis and later on develop a mixed gap and non-gaap acidosis the anion gap rarely exceeds 20 milliequivalents per liter even in advanced renal failure so seeing a gap of this severity should always prompt an investigation for an alternative explanation next are the toxic alcohols methanol ethylene glycol and propylene glycol starting with methanol it has various industrial uses is found in some windshield wiper fluid antifreeze and a paint remover although it's commonly taught that methanol poisoning is common in alcoholics who are using methanol in place of ethanol I personally believe the frequency of this is extremely small for the simple reason that ethanol is so much easier to obtain where methanol poisoning is seen however is accidental ingestion and in psychotic patients it can also be seen in suicide attempts but drinking paint remover seems like such an unpleasant experience I also have to believe this is relatively rare methanol can also be inhaled or directly absorbed to the skin which can be a source of industrial contamination symptoms of methanol poisoning include vision loss photophobia abdominal pain confusion and lethargy to briefly summarize the metabolism of methanol it first undergoes oxidation to formaldehyde with the assistance from alcohol dehydrogenase the same first step as with ethanol metabolism as all methanol is broken down into formaldehyde it might be assumed that formaldehyde toxicity has a very similar presentation however as formaldehyde is highly volatile human exposure is usually from inhalation and thus it predominantly causes pulmonary symptoms the next step in the metabolism of methanol is further oxidation to form eight or formic acid under regulation of the enzyme formaldehyde dehydrogenase in his formic acid that is actually responsible for both the increased anion gap acidosis as well as all of the pathology that methanol toxicity causes finally formic acid is broken down into carbon dioxide and water a reaction which requires the presence of tetrahydrofolate therefore it might seem logical that patients who are folate deficient are more prone to methanol toxicity and that folate administration might be a way to treat this condition but to the best of my knowledge neither has actually been proven ethylene glycol toxicity shares a number of features in common with methanol poisoning and utilizes very similar pathways ethylene glycol is a colorless odorless but sweet compound that is found in antifreeze and liquid coolants its sweetness is one of the reasons poisoning from it is disproportionately present in children and animals the symptoms of ethylene glycol poisoning is usually broken down into three stages first comes confusion within 12 hours of ingestion heart failure myocarditis and pulmonary edema develop at about 24 hours an acute kidney injury occurs 24 to 72 hours after ingestion as we will see with methanol in a few minutes an understanding of the metabolism ethylene glycol is important in understanding key features of its presentation as with all these alcohols the first step is oxidation by alcohol dehydrogenase in this circumstance the result is glyco aldehyde Coleco aldehyde is further oxidized by aldehyde dehydrogenase to glycolate glycolate is one of the direct contributors to the elevated gap acidosis seen with ethylene glycol however it also impairs cellular respiration at the mitochondrial level and thus results in a concurrent lactic acidosis finally after several additional steps glycolate is metabolized into oxalate oxalate forms complexes with calcium and these complexes are deposited into the kidney heart brain and lungs and is responsible for all the pathologic features not attributable to that lactic acid ethylene glycol toxicity is diagnosed from levels directly measured in the blood but strong supporting evidence includes the discovery of calcium oxalate crystals in the urine which can be seen on light microscopy and which is likely to be quicker to obtain an ethylene glycol level antifreeze which is the most common source of ethylene glycol poisoning usually also includes fluorescein added to help trace the source of leaks in automobiles flow seen when ingested by humans is eliminated via the kidneys as a consequence there is a long-held belief that looking for fluorescence when shining a UV light on urine can be helpful in making the diagnosis this particular photograph is from a case in the New England Journal of Medicine you're infom a patient with ethylene glycol poisoning is on the left and a normal control on the right although the sounds like a cool and interesting down and dirty bedside technique there are actually a number of concerns that this is a poor diagnostic test there is at least one high quality study that found on average there was no significant difference in qualitative or quantitative fluorescence in normal urine and in urine to which fluorescein was directly added there is however a type of lab error that may prove helpful in making an early diagnosis of ethylene glycol toxicity it's a consequence of the fact that there exists significant structural similarities between lactate and the ethylene glycol breakdown product of glycol a the method that some point-of-care analyzers utilize will confuse glycolate for lactates and report an erroneously high lactate level this is best described with a Radiometer 700 point-of-care analyzer lab analyzers on the other hand utilized a completely different method for measuring lactate 1 which is not the susceptible to this error also point of care testing with an ISTAT ABG analyzer also does not appear susceptible to this error therefore a large discrepancy between lactate levels simultaneously measured by different analyzers colloquially known as a lactate gap should raise suspicion for this diagnosis the final toxic alcohol to talk about in detail is propylene glycol this is used as a solvent for a number of IV medications including the rasa pam phenobarbital diazepam and phenytoin the typical presentation of propylene glycol toxicity is the onset of renal failure and an unexplained lactic acidosis in a patient who has been on continuous infusion of IV lorazepam for at least several days quickly propylene glycol oxidized first to lockdown to hide and then again to lactate thus the lactic acidosis eventually the lactate is cleared by conversion back into pyruvate and ex acceptable level a propylene glycol administration has not been formally defined but commentary in the literature recommends a limit of 69 grams per day in patients with normal renal and hepatic function which is the equivalent of seven milligrams per hour of the rasa PEM other drugs are not infused at high enough rates to lead to propylene glycol toxicity by themselves but will contribute to this problem if combined with IV lorazepam here is a summary of the metabolism of simple alcohols in the body the first step is always oxidation with alcohol dehydrogenase to form an aldehyde and the next step is further oxidation to form a carboxylic acid it's this carboxylic acid that costs most of the pathologies seen with toxic alcohols with the addition of oxalate which is also very problematic an important connection between these pathways that is clinically relevant concerns the fact that the affinity of alcohol dehydrogenase for ethanol is greater than that of methanol or ethanol historically this has been taken advantage of in treating methanol or ethanol in glycol poisoning with an ethanol infusion as this will slow down metabolism of the more toxic alcohols into their dangerous carboxylic acid forms a new alternative agent to ethanol is a drug called foam it boosts all which is a competitive inhibitor of alcohol dehydrogenase and which is generally considered safer than ethanol infusion but is not available in all facilities before we leave the topic of toxic alcohols I should discuss the serum osmolarity used to identify the presence of these compounds serum osmolality is predominantly determined by sodium bicarbonate chloride glucose and urea it can be estimated by taking two times the serum sodium and adding the B UN in milligrams per deciliter divided by 2.8 and the glucose in milligrams per deciliter divided by 18 the osmolar gap is the difference between the measured osmolarity and the calculated osmolality there is normally a small gap but accumulation in the serum of compounds of low molecular weight such as alcohols or to measure the serum osmolality above that calculated by the above equation small osmolar gaps are frequently seen in critically ill patients but are usually less than 20 millas moles per liter thus a gap greater than 20 strongly suggests the presence of an unmeasured Osmel particularly in alcohol this calculation is helpful because many labs will be able to result a serum osmolality faster than a serum methanol or ethylene glycol level general indications for determining the serum osmolar gap include suspected poisonings with an unknown toxin an elevated anion gap in the presence of a normal lactate ketones and renal function unexplained altered Mental Status particularly in alcoholic or child and periodic monitoring for patients on high doses of IV lorazepam there are a few compounds that can cause an elevated osmol gap without necessarily causing an elevated anion gap acidosis these include ethanol which is by far the most common cause of an osmolar gap isopropyl alcohol which is found in some brands of rubbing alcohol as well as the form of alcohol in most alcohol swabs diethyl ether which is an industrial solvent that was used as an early anesthetic in the late 19th and early 20th centuries and finally mannitol used to induce an osmotic diuresis or to reduce intracranial pressure in patients with certain neurologic - trophies before I finally move off of toxic alcohols there is one important limitation to using the osmolar gap in methanol poisoning demonstrated by this diagram for a patient who has had a single acute episode of methanol ingestion the concentration of methanol as a function of time is shown here in blue as methanol goes through its metabolism formic acid levels which are initially very low suddenly rise up after a period of time before dropping off as the rate of its breakdown starts to exceed that of its production if you remember I said that formic acid was the source the elevated 9 gap acidosis so it starts low and with time starts to rise unfortunately the source of the elevator Osmo low gap is the methanol which starts high and becomes low with time therefore there is a significant chance that the osmolar gap and the anion gap will not both be elevated at the same moment in time which is unfortunate since it is the combination of the two which is classically taught to be suggestive of this diagnosis furthermore the likelihood of a patient having symptoms is based on the formic acid levels so symptoms may not even develop until the osmolar gap has returned to normal the bottom line is to never rule out methanol ingestion on the basis of a normal a smaller gap so I'm finally done with alcohol and I promise we are almost to the ideologies just a few very quick ones left next is Halloween Halloween is an aromatic hydrocarbon commonly found in glues adhesives and paint thinner while there are many organic solvents that are available for abuse Halloween has among the highest abuse potential and is particularly common among children and adolescents where they get exposure from sniffing glue it has a complex and incompletely understood effect on neural chemistry but at least partially acts as an NDMA receptor antagonist similar to PCP letras oxide and ketamine which explains its prominent acute effects of euphoria loss of inhibition and amnesia in higher doses it can result in slurred speech ataxia seizures and coma in chronic abuse patients can develop cerebellar dysfunction and dementia as well as RTA or renal tubular acidosis profound hypokalemia and renal failure next is the most recently discovered cause of an elevated anion gap metabolic acidosis a naturally occurring metabolic intermediary called v ox o prolene v ox or prolene also known as pyro glutamic acid is part of an interesting metabolic derangement seen most exclusively in chronic acetaminophen abuse which blocks production of glutathione additional risk factors for developing actual anemia include advanced aged malnutrition chronic illness and alcoholism all of which are associated with low glutathione levels the symptoms and science of actual anemia are the nonspecific consequences of a severe metabolic acidosis diagnosis requires an organic acid screen of the urine and/or serum which can take weeks to be resulted to understand how chronic acetaminophen used leads to high levels of v Aqsa prolene it's necessary to give a very brief overview of the incompletely understood gamma glutamine cycle if you've already had your fill of biochemistry please feel free to skip ahead about 90 seconds the gamma gluten meal cycle is a sequence of pathways thought to be important in a variety of metabolic functions including transmembrane transport of amino acids and breakdown products of various xenobiotics that is the breakdown of compounds not normally produced or processed by the body I will skip most of the specifics of this cycle but there is one key enzymatic step to be aware of here where gamma glutamine cysteine synthetase catalyzes the conversion of glutamate the gamma glutamine cysteine activity of this enzyme is usually under negative feedback from glutathione however in patients on chronic acetaminophen glutathione levels are reduced this removes negative inhibition leading to excessive gamma glutamine cysteine which exceeds the capacity of the body to convert it into glutathione so instead it gets shunted through another pathway that is normally used only minimally that converts it back to 5 ox or prolene since conversion of 5 octa prolene to glutamate is relatively slow 5 octa prolene begins to accumulate at least this is the current theory as to how this happens the last ideology and definitely the least is para aldehyde as I mentioned earlier in the lecture apparel dehyde is actually part of the mud pilus mnemonic but no one actually uses power anymore so this is really just of historical interest only now power because so many people MIT law will still mention it on the differential diagnosis without really thinking it through or knowing exactly it is I just want to spend just a very fast minute talking about it so what is paranoid it is a sedative and anticonvulsant that was previously used as a sleep aid and to treat delirium tremens a usage dropped off in 1960s and 70s as safer alternatives such as benzodiazepines became more popular it is no longer manufactured in the United States and the mechanism for inducing metabolic acidosis was never actually determined I'm gonna return now to the modern mnemonics that will help you remember the ideologies of an elevated gap acidosis they are gold mark and Colt to remind you one more time gold mark is for glycols ox or prolene L lactate D lactate methanol aspirin renal and ketoacidosis and Colt is for ketoacidosis uremia lactic acidosis and toxins the last thing I will review is a general approach or algorithm to diagnosing the etiology of an elevated anion gap metabolic acidosis first step always be sure the anion gap is adjusted upwards for hypoalbuminemia please see lecture 5 for details on how to do that next check the ABG to confirm that the patient doesn't just have an elevated anion gap and low bicarb but actually has a metabolic acidosis as well if there is no acidosis you should consider causes of an elevated anion gap that don't cause an acidosis these include severe hyper phosphate emia and the presence of an anionic para protein assessment of the ph will also help to assess the physiologic severity of the acidosis as well as look for concurrent acid based arrangements which can be of assistance and determine the underlying etiology once an actual acidosis is confirmed to be present check lactate and ketone levels as these are the most common causes of an elevator anion gap acidosis if lactate is elevated assess for the presence of hypoperfusion if hypoperfusion is present and systemic the anion gap acidosis is likely a consequence of shock if there is evidence of regional hypoperfusion then the cause of lactic acidosis is related to that if there is an elevated lactate but no hyper perfusion anywhere you should strongly consider a medication side effect toxic ingestion or lactate producing tumor at this point if there is any altered Mental Status or a history that is potentially compatible with toxic ingestion a urine tox screen salicylate in acetaminophen levels and an osmolar gap calculation are all indicated even if it seems that lactic acidosis is the sole cause of the acidosis you're seeing if instead of an elevated lactate ketones are present and if the glucose is greater than 250 the patient likely has DKA whereas if the patient is a heavy alcoholic then alcoholic ketoacidosis is the probable diagnosis if both lactate and ketones are normal look at the renal function at GFR less than 40 and anion gap less than 20 suggests that renal failure alone might be the explanation however if the either the GFR is greater than 40 and or an anion gap is greater than 20 check the osmolal gap if that is greater than 20 you may be dealing with a toxic alcohol if the osmolar gap is less than 20 consider rare ideologies as well as a late presentation of methanol poisoning the absolute last point to make here is that the ideologies for an elevated gap acidosis are absolutely by no means mutually exclusive it is in fact quite common for these to coexist in the same patient which can impinge in our ability to figure out what's going on so that's it for the ideologies of an elevated gap metabolic acidosis if you're still with me at this point I applaud your thirst for knowledge and hope that you continue on to lecture 9 which will cover normal anion gap acidosis and which I promise will contain much less biochemistry [Music] you

Channel: Strong Medicine

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Keywords: elevated anion gap, metabolic acidosis, lactate, lactic acidosis, ketoacidosis, dka, ketone bodies, oxoproline, toluene, methanol, ethylene glycol, antifreeze, propylene glycol, paraldehyde, shock, arterial blood gas, abg, stanford, medical lecture, metformin, differential diagnosis, mudpiles

Id: CmQOtP3pFus

Length: 42min 45sec (2565 seconds)

Published: Mon Apr 09 2012