[Music] [Applause] hello this is Eric Strong from the PaloAlto VA and Stanford University and this is the 20th and final lecture in this course on understanding AGS the title of this lecture is bringing it all together using the AG to create a unified model of human pathophysiology and that's what I hope to do the specific learning objectives are first to become familiar with the measurements of total blood oxygen content abbreviated Ca O2 and oxygen delivery abbreviated DO2 second to have the an understanding of how the same knowledge used in analysis of an AG can also be used to create a unified model of pathophysiology and finally to be able to incorporate ABG interpretation into strategies for diagnosing a wide range of pathologic conditions to create our unified model of pathophysiology I will first need to explicitly state the fundamental principle of human physiology this is what all of the preceding 19 lectures have been driving towards the primary purpose of human physiology is to enable aerobic respiration by delivering oxygen to cells and by removing carbon dioxide from cells all organ systems and individual biochemical processes exist to support this purpose for example most obviously the purpose of the lungs is to assist with this exchange with our outside environment and the purpose of the heart is to pump the blood around the body carrying these gases to and from the lungs but consider what the purpose of the GI system is it is to bring in carbohydrates and fats which can be converted to glucose or other precursors of the KB cycle which will then be ultimately used to drive oxidative phosphorilation and the primary purpose of the neurologic system which is to allow people to move around in the world and acquire the food that is then introduced into the GI tract i'll acknowledge that this is extremely reductionist but this is what our bodies ultimately do whether or not you realized it at the time I have already reviewed the majority of the biochemical processes and systems which support aerobic metabolism but there is one or two pieces left before we can fit everything together into a cohesive hole those final pieces are the final steps of how oxygen gets from air into our cells we have already reviewed the process of ventilation by which oxygen enters the alvoli and diffusion where oxygen moves from the alvoli into the pulmonary capillaries the last lecture covered transport that is how oxygen binds to hemoglobin the remaining steps are how oxygen is delivered to the organs and peripheral tissues and then how oxygen is extracted by cells at those locations let's talk about the oxygen content in blood this was addressed informally in a couple of lectures already but let's try to formalize a process by which we assess how much oxygen is contained within a sample of arterial blood arterial oxygen content abbreviated C little AO2 is equal to the sum of oxygen bound to hemoglobin and oxygen dissolved in blood the amount of oxygen bound to hemoglobin is equal to 1.34 which is the maximum oxygen carrying capacity in milliliters of oxygen per gram of hemoglobin times the hemoglobin concentration times the oxygen saturation although most textbooks use the term s little ao2 to describe oxygen sat in this equation for reasons discussed in the last lecture i personally prefer this percentage O2 hemoglobin the oxygen dissolved in blood is equal to 0.003 which is the solubility constant of oxygen times the partial pressure of oxygen let's plug in numbers for a typical healthy adult 14 g per deciliter for hemoglobin an O2 sat of 98% and a P little AO2 of 100 millm of mercury multiplying these numbers out we find that in 100 milliliters of blood about 18.4 milll of oxygen is bound to hemoglobin and 0.3 milll of oxygen is dissolved in blood in other words the amount dissolved in blood is negligible in most circumstances therefore we can approximate C little AO2 as 1.34 time hemoglobin concentration times the oxygen sat even though this value is traditionally called the oxygen content it would be more accurate to call it oxygen concentration there is a closely related physiologic parameter called oxygen delivery abbreviated DO2 do2 is the rate at which oxygen is brought to the peripheral tissues when discussing the DO2 for the entire body it is equal to the cardiac output times the oxygen content cardiac output is a concept which we have not explicitly discussed during this course but which is reviewed in my lecture on shock uh also available on this channel succinctly cardiac output is the flow of blood from the heart to the body and units of volume per unit time it is primarily dependent on four things the heart rate intravascular volume sometimes called preload in this context myioardial contractility and something called afterload we can also discuss oxygen delivery on a regional level in which DO2 is equal to the blood flow to the region of interest designated Q times CAO2 in addition to dependence on cardiac output Q is also dependent upon the presence or absence of malistribution of blood flow in an obvious example if a blood clot embleizes to an artery of the gut a person could end up with impaired delivery of oxygen to the corresponding segment of gut despite the body's overall cardiac output being intact in a less obvious but nonetheless more common example a patient with septic shock has systemic vasoddilation which there is low resistance present in blood vessels that travel to non-essential parts of the body like the extremities and atapose tissue these lowresistance vessels shunt blood away from critical areas like the brain and kidneys resulting in organ dysfunction and a switching from aerobic respiration to anorobic respiration that is metabolism that does not require oxygen so now having briefly covered the concepts of oxygen content and oxygen delivery let's take all of the information learned throughout the entire course and assemble it into a unified model of pathophysiology as I stated earlier the enabling of aerobic respiration is the foundation of physiology so I'm going to place that in the middle here and the link to pathophysiology is the balance it has with anorobic respiration around this balance I'm going to lay out the four fundamental domains of physiologic processes that we are able to directly analyze using the AG first is acid base balance most fundamentally dependent upon the kidney and concisely summarized mathematically by the Henderson Hasselbach equation next is ventilation which requires communication between central and peripheral chemo receptors the respiratory centers of the brain and the lungs the process of ventilation is summarized by the alvolar ventilation equation here continuing around there is oxygenation also dependent on the lungs there are two fundamental mathematical relationships involved with oxygenation the alvolar gas equation and the simple formula for determination of the AA gradient finally our last domain is oxygen transport and delivery these closely related processes are defined by the oxygen hemoglobin dissociation curve the formula for oxygen content and that for regional oxygen delivery this model will feel incomplete if we don't also include two aspects of physiology that have been discussed only in passing and which are not the focus of this course per se the first is the intravascular volume that is is the body's tank for empty the second is the cardiac function there are many many ways to describe cardiac function but I will choose to summarize it as cardiac output equals stroke volume times heart rate where the stroke volume is the quantitative measure of the volume of blood ejected from the heart with each contraction a viewer who is tuning in here halfway through the final lecture in this course on AGS would likely be surprised to see the cardiovascular system superficially appear to play a much more minor role in physiology compared to the pulmonary and renal systems however I want to stress that this model is being created through the lens of AG analysis a model created by a cardiologist from the viewpoint of the heart would look quite different it wouldn't necessarily be better or worse just an alternative approach to understanding the complex system that is the human body let's now take a look at how all these individual pieces are interconnected starting with acid base balance since that's where our course began through multiple mechanisms within the kidney ph feeds back and helps to regulate serum bicarbonate concentration bicarb also be impacted by intravascular volume most prominently in the case of a contraction alkyossis where volume depletion leads to concurrent retention of sodium and bicarbonate ion and loss of hydrogen ions low pH is sensed by peripheral and central chemo receptors which leads to an increase in ventilation by increasing both the respiratory rate and tidal volume the latter of which is possibly more affected ventilation in the form of PA CO2 directly feeds back to the Henderson Hasselbach equation pa CO2 also directly impacts the respiratory rate and to lesser extent tidal volume as yet another means of feedback ventilation and oxygenation are linked in two specific ways first the Pa CO2 is directly inputed into the alvolar gas equation second low P little AO2 stimulates ventilation continuing our way around the diagram P little AO2 is also the primary determinant of O2 saturation via the oxygen hemoglobin dissociation curve however low pH high pa CO2 and high 23 DPG all cause a rightward shift of that curve which will assist with oxygen unloading in peripheral tissues returning to the status of intravascular volume in addition to directly linking with acid base balance the primary effect of volume is actually on determination of stroke volume which helps to determine the overall cardiac function the specific relationship between intravascular volume and stroke volume is actually quite complex as increases in intravascular volume can cause either an increase or a decrease in stroke volume depending upon where you're starting from the cardiac output with influence of blood flow distribution determines perusion of different organs or regions of the body perfusion combined with the oxygen content are the determinants of oxygen delivery and ultimately it is oxygen delivery to our cells relative to their oxygen demand that is the principal driving force behind keeping their metabolism aerobic another important factor to consider is that extreme derangements in pH will lead to enzyme dysfunction which can result in anorobic respiration and there are two specific and clinically relevant ways in which respiration communicates back to the individual components of the system first aerobic respiration directly produces carbon dioxide as a byproduct which will impact Pa CO2 and second anorobic respiration results in the production of lactic acid what are the downstream effects of lactic acid lactic acid will of course drive down by cararb which drives down pH which increases ventilation which lowers pa2 which increases p big a2 which increases p little a2 which increases o2 sat which increases ca2 which increases d2 which works to ultimately drive respiration back to the aerobic side so you can see that everything is quite interconnected i'm now going to concisely summarize a general approach to complete AG analysis while you can start with either the acid base or the oxygenation component of the AG I think it is slightly easier to start with oxygenation when evaluating oxygenation first check the AA gradient and then compare it with a normal or expected AA gradient which is dependent upon primarily age but also on the amount of supplemental oxygen a patient is receiving finally check the saturation gap that is make sure that there is less than a 5% difference between the O2 sat measured by pulse occimmetry and the O2 sat calculated from the AG part two is to evaluate acid base status the first steps here are to check the pH and the pCCO2 to determine the first disorder next check the appropriateness of compensation to look for a second disorder then check the annion gap finally if the annion gap is elevated check the delta ratio to look for a second or third disorder part three is to generate a differential diagnosis for each abnormality of oxygenation and/or acid base balance acquiring additional information as necessary such as lactate levels and chest X-ray findings lastly create a final summitive diagnosis that links everything from part three together if at all possible for the remainder of the lecture I'm going to go through three example cases each of which comes with an ABG these cases are complicated and analyzing them will require knowledge from most of the preceding 19 lectures then I will map out on the unified model exactly how the various physiologic abnormalities relate to one another schematically i hope these examples will solidify your understanding of AVG analysis and more broadly human pathophysiology i recommend intermittently pausing the video as the examples are reviewed in order to test your own skills at analyzing the clinical scenarios example number one a 92year-old woman is sent to the ER from her nursing home after she developed a fever and dispnia several hours ago on arrival to the ER her temperature is 102.6 6 heart rate is 125 blood pressure 76 over 48 respiratory rate 30 and O2 sat via pulseox is 85% on roomair she is in respiratory distress and is incoherent her exam is otherwise notable for decreased breath sounds of the right lung base her jugular venus pulsations are flat and her extremities are warm here is her AG I prefer to start with looking at the oxygenation The first step with this will be to check the AA gradient to do this start with a determination of the alvular oxygen tension designated P big AO2 which we can do using the alvular gas equation the first term for a patient breathing room air at sea level conveniently reduces to 150 and we plug in 25 for the P little A CO2 and we get a P big A O2 of 119 mm of mercury the gradient will be the difference between this value and measured P little AO2 which is 72 step two estimate the normal or expected AA gradient the common form of this estimation looks like this where the normal AA gradient is approximately equal to the patient's age divided by 4 + 4 and then in lecture 17 I discussed why we need to add this additional term which accounts for worsening a VQ mismatch as a consequence of supplemental oxygen overcoming adaptive hypoxic baso constriction this extra term will be equal to zero for a patient on roomair so her gradient here specifically becomes 92 / 4 + 4 which is 27 comparing 27 to 72 we immediately see that she has an elevated AA gradient hypoxmia step three check the saturation gap as we discussed in lecture 19 this is the absolute value of the difference between the O2 sat measured by pulseox or SPO2 and the O2 sat calculated by the AG analyzer or S little A O2 here that gap is 2% anything less than 5% is considered normal let's move on to discuss her acidbased status step one her pH is slightly alkalic step two her pCCO2 is low so this alkalmia is the consequence of a respiratory alkalossis step three will be to evaluate her compensation if you remember back uh way back to lecture four I discussed a series of equations and rules of thumb for evaluation of compensation in the case of an acute respiratory alkalossis the by carb should be approximately 2 mill equivalents per liter lower than normal for each 10 m of mercury the pCCO2 is above normal in this case a pCCO2 of 25 would predict a bicarb of about 21 and although there is no specific rule about how close the actual by carb should come to the predicted I think 17 seems just a tad too far from 21 so I would actually label this to be inappropriate compensation since the bicarb is lower than predicted it suggests the presence of a concurrent metabolic acidosis this metabolic acidosis is not compensation for the respiratory alkyossis but is rather a separate primary process step four check the annion gap as discussed in lecture five this is equal to the sodium minus the sum of chloride and bicarb and helps to determine the presence of a pathologic unmeasured annion here are the relevant electrolytes and plugging in these numbers we find an annion gap here of 20 we then need to adjust the annion gap in the presence of hypoalmia using this empirically derived formula this patient's albamin is 2.5 which results in an adjusted anni gap of 24 therefore we now know that the metabolic acidosis identified in step three must be an elevated gap metabolic acidosis finally step five since the nine gap is elevated we should check the delta ratio as discussed in lecture six this is equal to the change in nine gap from normal which we typically say is 12 divided by the change in by carb from normal which we typically say is 24 plugging in our numbers we get 12 / 7 which is 1.7 if you recall from lecture six interpretation of the delta ratio requires to have a hypothesis about the likely ideology of acidosis but most ideologies generate a delta ratio between one and two with the exception of keto acidosis therefore this delta ratio of 1.7 is appropriate given that we know for a fact that an elevated metabolic acidosis is present in other words there is no third acidbased disorder at this point let's come up with a differential diagnosis for each of these various physiologic abnormalities first up the elevated AA gradient hypoxmia although I presented a basic algorithm for this in lecture 18 in practice all that will tell us is whether or not there is a shunt contributing to the hypoxmia to get an actual diagnosis we just need to use our brain a bit and go back to the history and exam for this patient the most prominent feature of the presentation is fever uh shortness of breath and typnia this most clearly suggests pneumonia but could also be due to a pulmonary embolism and the combination of sepsis and ARDS along with a dozen other theoretical possibilities the next step will be to check a chest X-ray which in this case reveals consolidation of the right middle and right lower loes so this is probably due to pneumonia next up the respiratory alkalossis this one's easy it's just the hypoxmia because the low PAO2 will in itself stimulate the brain's respiratory centers to breathe faster and deeper than normal finally is the elevated annion gap metabolic acidosis based on an algorithm presented in lecture 8 start with checking the lactate and ketones in this ketones are negative but lactate is severely elevated at 5.5 millm moles per liter so what's the ideology of lactic acidosis on the most fundamental level this is asking whether there is systemic hypoprofusion present regional hypoprofusion or no hypoprofusion given the clinical scenario including severe hypotension and warm extremities systemic hypoprofusion seems most likely when this is combined with sepsis we can better state the cause of the lactic acidosis as septic shock now we're almost at the end of the case the last step is to give a final summitive diagnosis here I'd say the patient has septic shock secondary to healthcare associated pneumonia since she's from a nursing home complicated by hypoxmia and lactic acidosis although this is how I would personally summarize her diagnosis there are many other ways that one could construct this with equal degree of correctness for example we could list her final diagnosis as healthcare associated pneumonia complicated by septic shock depending upon your area of practice this difference may be important for building or coding but for conveying useful information both of these say the exact same thing how does this woman's pathology map out on our model i'm going to designate the primary problems with a red box and the secondary problems with a tan box so her primary problems are an increased AA gradient caused by pneumonia and decreased profusion caused by sepsis induced malistribution of blood flow secondary problems are the respiratory alkyossis caused by hypoxmia induced stimulation of ventilation a change in the O2 sad as P little AO2 is the primary determinant which will subsequently affect CaO2 and finally her lactic acidosis produced by anorobic respiration will decrease the serum by carb which will then lower the pH further we'll go through the other two cases a little more quickly example two a 45year-old man is found unconscious in a park on arrival to the ER his temperature is 97.5 heart rate 115 blood pressure 80 over 48 respiratory rate six and O2 sat 75% on room air he is disheveled and comeosse aside from his vital sign abnormalities and non-visible JBP pulmonary and cardiac exams are normal extremities are cold and mildly cyanotic here is the AG i'll start with oxygenation again step one check the AA gradient plugging in the numbers the P big AO2 is equal to 63 mm of mercury therefore the AA gradient is 63 minus 46 which is 17 step two estimate the normal AA gradient we'll use the same equation as last case which is 45 / 4 + 4 which is 15 15 is close enough to 17 to say that they are approximately equivalent therefore this patient has a normal AA gradient hypoxmia step three check the saturation gap the absolute value of 75% minus 77% is 2% which is normal next acid base status step one the pH tells us the patient has an academia and in step two the high pCCO2 tells us that the academia is at least in part due to a respiratory acidosis when we evaluate the compensation in step three we don't even need to know the specific equation since appropriate compensation for respiratory acidosis should result in a higher than normal by carb and our byarb is lower than normal we know that a primary metabolic acidosis must be present step four calculate the annion gap here are the patients electrolytes which gives us an annion gap of 25 we then see the patient's albumin is two as a consequence our annion gap is adjusted upward to 30 so this patient's metabolic acidosis is an elevated gap acidosis step five calculate the delta ratio plugging in his numbers gives us a ratio of 2.6 2.6 is elevated irrespective of the ideology of the elevated gap in other words the bicarb concentration is not as deranged as it would be expected just from accumulation of an unmeasured annion therefore there must be also a metabolic alkyossis present that is pushing the bicarb higher than it would be otherwise differential diagnosis the normal aa gradient hypoxmia is easy hypoventilation which has the same differential as the respiratory acidosis among all patients the most common ideologies of a respiratory acidosis are COPD asthma obesity hypoventilation syndrome and drug intoxication or overdose given the clinical scenario it seems prudent to start with looking for drugs a urine toxine is positive for opiates and bzzoipines and a serum ethanol level is severely elevated at 350 milligrams per deciliter that's more than four times the legal limit for driving here in California so the patient has a drug overdose don't forget to check for other common drugs and poisonings the ease of which may depend upon your institution's lab at our lab our salicellate and acetaminophen levels are easy and quick and in this case are both negative next is the elevated gap acidosis from the last case you know that the first place to start is with lactate and ketones in this case lactate is elevated and ketones are positive so why does this patient have a lactic acidosis the exam and overall picture suggests systemic hypo proferusion either from sepsis hypoalmia or both also as discussed in lecture 8 people have a much higher propensity towards lactic acidosis when acutely intoxicated with alcohol why does this patient have a keto acidosis major causes of a keto acidosis are diabetes and alcohol just to be sure he doesn't also have the former we should check a serum glucose which I'm sure in reality would have been done during his first several minutes in the ER in this case glucose is normal at 85 milligrams per deciliter therefore this patient's keto acidosis is just from alcohol finally the metabolic alkyossis the differential diagnosis for this depends very strongly on volume status and history as volume status as previously stated seems to be low and based on the history a contraction alkalossis from dehydration seems quite plausible though we couldn't rule out concurrent vomiting as he is currently unable to report this to us so in summary the patient has an overdose of alcohol opiates and benzoazipines resulting in a severe respiratory acidosis and hypoventilation associated hypoxia as secondary diagnosis he has a lactic acidosis secondary to hypoxmia acute ethanol intake and hypoalmia plus or minus septic shock he also has alcoholic keto acidosis and last he has a metabolic alkalossis likely secondary to dehydration plus or minus vomiting in our model his primary abnormalities are low respiratory rate from drug overdose low by carb from his ketoacidosis low intravascular volume and possibly low profusion secondary to sepsis induced malistribution of blood flow secondary effects include low stroke volume from the dehydration production of lactic acid through multiple mechanisms elevated PA2 on account of the low respiratory rate hypoventilation associated hypoxmia and lastly a contraction alkalossis helping to blunt his low serum by cararb our third and final example a 48-year-old man with AIDS and depression is brought to the ER after he was found unconscious by a friend surrounded by empty pill bottles on arrival he is comeomaosse and cyanotic vitals temp 99.5 heart rate 105 BP 95 over 45 respiratory rate 30 O2 sat via pulse ox 87% on 10 L of oxygen via face mask the remainder of the exam is normal and here is his AG on 10 L of oxygen step one the AA gradient in this case the patient is not on room air but on 10 liters of oxygen via simple face mask there is no reliable means to determine his FiO2 but based on published empirical data we can roughly estimate this as 60% which is the maximum practical amount of O2 that can be delivered via simple face mask plugging in our numbers gives a P big A O2 of 403 and a gradient of 33 to estimate the expected AA gradient we will actually need to use that extra term at the end of the equation so we have 48 / 4 + 4 + 20 which is 36 36 is close to 33 so there is not an elevation of the AA gradient an interesting question is whether the patient is even hypoxmic the O2 sat via pulseox suggests he is but the P little A O2 is extremely high which means he's not actually hypoxmic this leads us right to the saturation gap you may have already noticed this but with step three we see that the saturation gap is elevated at 13% the reason for this might be obvious but I'm going to come back to it in a minute acid base check the pH it's normal but that certainly does not mean the patient does not have an acid base abnormality looking at the PCCO2 and by carb we see that they are both severely decreased the only explanation is the concurrent respiratory alkalossis and metabolic acidosis the pH is only normal because by pure chance the effects on pH of these two disorders perfectly balance next check the annion gap which here is 15 with the adjustment for his albamin of two this becomes 20 so the metabolic acidosis already identified is an elevated gap acidosis since the annion gap is elevated we check the delta ratio which is calculated to be 0.7 this is too low in other words the by carb is lower than it should be if only acid base problem is too much unmeasured annion therefore there is also a normal gap metabolic acidosis present now our differential diagnosis let's start with the obvious the saturation gap the combination of an SAO2 much greater than SP2 and cyanosis occurring at a relatively modest decrease of SPO2 must be the consequence of met hemoglobinia there's nothing else that will do this but if you would still want to confirm it with a met hemoglobin level uh we can check it here which is 35% in other words 35% of all circulating hemoglobin has had one of its iron ions oxidized from the plus2 state to the plus three state this is almost always a consequence of medication toxicity since our patient seems to have taken an overdose checking his medication list is a good place to start looking at his medical chart we would see that his outpatient med list includes some anti-retrovirals Bactrum for PCP prophylaxis and aspirin guess what the sulfomthoxisol in Bactrum often abbreviated SMX has been linked to the rare side effect of met hemoglobinia which is probably dose dependent and thus much more likely in the setting of an overdose unfortunately there is no commercially available test for sulfomthoxisol levels so this diagnosis will be to some extent presumptive next we have the respiratory alkalossis here's a near complete list of possible ideologies divided into common and uncommon since we've just diagnosed a patient with met hemoglobinia we know that the oxygen content in the blood is poor triggering hyperventilation though as recently stated it isn't technically hypoxmia per se in addition to the oxygenation issues we also have aspirin toxicity on the list and given that aspirin shows up on the patient's medication list it is obviously prudent to check a salicellate level which in this case is in the toxic range at 3.5 millm moles per liter moving on we have the elevated nine gap acidosis once again check lactate and ketones ketones negative lactate very elevated at 5.5 millm moles per liter so why is lactate elevated is hypoprofusion systemic regional or non-existent in this case I think it's impossible to say with certainty whether the problem is systemic impairment of oxygen delivery on account of the met hemoglobinia or if the problem is poisoning of mitochondria on account of the salicellate toxicity it's probably a little of both finally there is the normal anine gap acidosis for this the first step is to check the creatinine this patient's creatinine is significantly elevated at 3.5 which is presumably acute since we are told nothing to suggest he has chronic kidney disease acute kidney failure is well described in the setting of both psilicate and bactrum toxicity although all of our pathophysiology is accounted for given the nature of his situation it would also be prudent to check for the presence of other drugs so for example a urine toxine and acetaminophen level just to be sure that we haven't missed anything so our final diagnoses are number one met hemoglobinia secondary to presumed bactrum overdose number two lactic acidosis secondary to aspirin overdose and or met hemoglobinia number three acute kidney injury secondary to aspirin or uh bactrum overdose and four respiratory alkalossis secondary to aspirin overdose and or hemoglobinia this list sounds quite cumbersome so I probably would further synthesize it and instead describe the patients diagnosis more succinctly as an overdose of aspirin and presumed spectrum resulting in met hemoglobinia lactic acidosis acute kidney injury and a primary respiratory alkalossis mapping this out because of the salicellate toxicity a direct impairment of aerobic respiration is actually a primary problem along with the derangement of the oxygen hemoglobin dissociation curve due to the met hemoglobinia the bicarbonate because of the renal failure and ventilation due also to the salicellates prominent secondary effects include an abnormally low oxyhemoglobin percentage and an excessive production of lactic acid which further impacts the byarb if you're feeling a little lost after these examples please don't be too alarmed these are in fact among the most complicated AG related diagnoses you'll ever need to make in practice so that's it that's the end of this lecture on bringing it all together and the end of this course on understanding ABGs so if you made it through all eight hours congratulations i applaud your enthusiasm for learning and I hope you found it time well spent please feel free to post comments or ask questions and also check out the other videos on this channel [Music]