6 paltry nuisances and the histrionic ire they beget...

Join me as I first discuss annoying people, followed by a lot of annoying Medicine.

Bajaj JS, Pyrsopoulos NT, Rahimi RS, Heimanson Z, Allen C, Rockey DC. Serum Ammonia Levels Do Not Correlate With Overt Hepatic Encephalopathy Severity in Hospitalized Patients With Cirrhosis. Clin Gastroenterol Hepatol. 2024 Sep;22(9):1950-1952.e1.

Carlberg B, Samuelsson O, Lindholm LH. Atenolol in hypertension: is it a wise choice? Lancet. 2004 Nov 6-12;364(9446):1684-9. 

Espinel CH. The FENa test. Use in the differential diagnosis of acute renal failure. JAMA. 1976 Aug 9;236(6):579-81.

Hirota T, Fujita Y, Ieiri I. An updated review of pharmacokinetic drug interactions and pharmacogenetics of statins. Expert Opin Drug Metab Toxicol. 2020 Sep;16(9):809-822.

Osa-Andrews B, Sanchez M, Hashim IA. The Continued Need for the Routine Assessment of Folate Status. Lab Med. 2023 Jul 5;54(4):424-428.

Pan HC, Jiang ZH, Chen HY, Liu JH, Chen YW, Peng KY, Wu VC, Hsiao CC. Assessing the utility of fractional excretion of urea in distinguishing intrinsic and prerenal acute kidney injury in hospitalised patients: a systematic review and meta-analysis. BMJ Open. 2026 Jan 14;16(1):e100875.

Ripley TL, Saseen JJ. β-blockers: a review of their pharmacological and physiological diversity in hypertension. Ann Pharmacother. 2014 Jun;48(6):723-33.

Sobczyńska-Malefora A, Harrington DJ. Laboratory assessment of folate (vitamin B9) status. J Clin Pathol. 2018 Nov;71(11):949-956. 

Varghese V, Rivera MS, Alalwan A, Alghamdi AM, Ramanand A, Khan SM, Najul-Seda JE, Velez JCQ. Concomitant Identification of Muddy Brown Granular Casts and Low Fractional Excretion of Urinary Sodium in AKI. Kidney360. 2022 Jan 19;3(4):627-635.

Wiysonge CS, Bradley HA, Volmink J, Mayosi BM, Opie LH. Beta-blockers for hypertension. Cochrane Database Syst Rev. 2017 Jan 20;1(1):CD002003.

Transcript

SPEAKER_00 0:14

Hiady ho, friends and neighbors. I'm back. It's late at night, and I'm exhausted from a long day at work and from just existing in the world we live in right now. I'm generally a pretty optimistic, silver lining kind of person, but let's all be honest, sometimes it's easy to get dragged down and stomped on. In these trying times, I am so thankful for my amazing colleagues, residents, and patients at Best Boise Hospital and their ability to always put a smile on my face and in my soul. But I will admit, I do occasionally encounter assholes. At this point in my career, I can take whatever crap most people want to hurl my way. I'm practically an asshole whisperer. And I like the patients with a bit of spice. Most of my patients are quite old, and I find it very hard to get offended by anyone over the age of 90. Most of the time it's just sort of cute. The more cantankerous, the better, really. And if they threaten to hurt me, well, they don't move very fast, so plenty of time to get out of the way. If they can hit me with spit, well that probably means they have good lungs and a strong cough. Let's celebrate their low risk of pneumonia. I once cared for a very small, very frail, wispy slip of an older gentleman in the ICU who was upset about something or other with his care, and he told us that if things didn't change, he was going to get up and leave. Now he hadn't walked in years, couldn't even lift a fork, and what I was thinking was, okay, sir, see how that works out for you. But you don't want to be a jerk and you want to preserve their dignity, so instead I said something like, Please don't go, sir. I really hope you stay and we can work together to improve things. And then he asked me to hold a tissue to his face so he could blow his nose because he couldn't lift up his arm. Dealing with rude patients is a rite of passage during internear, and it is harder than any medicine rotation you have to conquer. Because while the patient is accusing you of being stupid and not doing the right thing, you are still every minute of every day thinking, am I stupid? Am I doing the right thing? The first time I had a patient ask for a change of provider because I wouldn't prescribe a medication that wasn't indicated, that was devastating. I should have known this was coming since just two months prior, she told me I was the most amazing doctor she'd ever had, and that I was the first one who'd ever really listened to her, and she was so sure I would be the one to help her. Rookie mistake. I will never forget the first time I was really berated in person. It was in clinic, and I had spent at least an hour pre-charting on a particular patient I was taking over, going through all the outside hospital records and prior clinic notes and trying to decide which of all the active and untreated medical issues needed to be prioritized. This patient had a lot of psychosocial challenges. Armed with eagerness and empathy, I was going to save her. Well, she came in and immediately started to tell me about how her wrist was hurting and needed surgery, which she had mentioned to the receptionist as the reason for her visit. And wasn't I going to give her some medication for the pain? And then why hadn't I already set up surgery? Because otherwise it was a waste of time for her to have come to see me. And obviously, I didn't know what I was doing because I wasn't treating her pain and didn't have the surgery set up in advance. I don't remember at all how the visit ended. I only remember my face starting to flush. And then flushing even more as I became aware that it was flushing and feeling sweat on my upper lip as I realized that she could probably see that I was flushing and now sweating. But she did eventually leave, apparently, because it's 10 years later and I'm not still in that office. I do remember feeling like a 100% failure and wondering, oh my god, did I screw up? Should I have set up that surgery? The answer, by the way, is no. I was on a roll that month because just a few short weeks later, I had another troubling encounter with a patient who came in for an episodic care visit. He gave me this whole big spiel about something or other and was super chummy and winky until the end when he asked for benzos. I said no. I think the only words I actually said during that entire encounter were, I can't prescribe those for you because I'm not your regular doctor. But he unloaded. All of a sudden, I was the worst doctor ever, and my training program was garbage, and his other doctor, who was Harvard trained, thought benzos were a good idea, and he could tell that I was a bitch from the minute he walked in. And I just remember being like, wait, what? What is happening? And I just sat there and stared at him. And after he was done telling me what a piece of crap I was, he stormed out. Apparently he didn't know that Harvard sucks at diagnosing cellulitis, or he might not have so breezily thrown the name around. Now, when a patient is questioning my knowledge, I explain things back in the most technical terms possible, and they usually stop. Then there are the patients who are not only jerks, but also inappropriate and gross. Pretty much exclusively men. I've had patients offer me the privilege of spanking them for their birthday. I'm very careful now about whom I give hugs to, as I've had a few that held on just a bit too long for comfort. But the worst was my first month on an inpatient service as an intern, and a patient I nicknamed the Silver Fox, because he was still tall and good looking at age 80, albeit with an active herpes outbreak on his lower lip. He'd been a commercial airline pilot in the 60s and 70s, and you just knew he'd been a ladies' man. Every day he would remind me he was full code as long as it was me giving him mouth to mouth. He would also frequently invite me to sit on his lap and I would politely decline. I had never encountered this kind of situation before, and I had no idea what to do about it. The nurses had it worse because at one point we had to place a foley catheter for urinary retention, and apparently he would make dirty comments when the nurses had to do foly care. I did try to tell him to stop harassing the nurses, but he said he definitely didn't say anything lewd to them. Just to me, then I said, That's right, he said, and winked and smiled his herpy smile. And then there are the patients driven by spite. You know the ones. I had a 15-minute circular conversation once with a patient who was pissed that we couldn't provide a service listed on the website. I was like, but we don't have that. If I could get it for you, I would. But it says that you have it on the website and I need it. I understand that, and I'm really sorry, but there isn't anything I can do because we just don't have it. Nobody gets it. I want to talk to your supervisor. Yes, absolutely, but they will tell you the same thing. Okay, well, I'm calling the CEO. Okay, yes. Please do and let them know the website isn't accurate, so jerks like you are calling me and ruining my day. I didn't actually say that last part. My most favorite patient fueled by spite was a little old demented lady in our post-acute care unit who you just knew had been asking to talk to the manager her entire life. She had a broken hip but insisted on walking around on it anyway. No pain meds required. If you did something to piss her off, she would write your name down in her little book because she was demented and she'd forget it if it wasn't written down. Then, every time you'd go into her room, she would check your name against the names in her little book so she could remember if she didn't like you. Now that's some grit and clever problem solving. Respect. I would be lying if I said I didn't harbor my own small bit of rage under the surface. There are a lot of things people do in medicine that annoy me. I'm going to use this episode to expose all the nuisance issues that aren't major enough to warrant their own episodes.

Annoyance 1: misuse of NSTEMI

SPEAKER_00 7:26

Annoyance number one. Misuse of the diagnosis type 2 end STEMI. So there is this thing, many people do not know it's a thing, called the Universal Definition of Myocardial Infarction. It is the product of a collaboration between the European Society for Cardiology and American College of Cardiology, and is endorsed by the AHA and World Heart Federation, and has been adopted by the WHO. Okay, so we're no longer part of the WHO, but it isn't because of their shoddy science. And it is now in its fourth iteration because cardiologists change their minds about things a lot. So many. Do this right now, then just kidding, but truthfully, that's all medicine. Why do we need an official definition? Well, it lets us communicate using a shared understanding. This is particularly important for research. It also appears that they were just as annoyed as I am with the flippant and incorrect use of the term MI in some settings. So what is the definition of MI? Well, criteria really. First, there must be a rise and fall in troponin with at least one value above the upper limit of normal. But that's not enough. You must also have at least one of the following symptoms like chest pain or other anginal equivalent like dyspnea, maybe for some, new evidence of ischemia on EKG, new wall motion abnormalities on echo, or a thrombus actually identified in a vessel on angiography or autopsy. Pretty clear and straightforward. But it doesn't seem to be, because there are a ton of patients who get admitted to the hospital with an elevated troponin who end up with a diagnosis of type 2 NSTEMI or demand ischemia. But those patients don't meet any of the other criteria beyond the rise and fall of troponin. So what do those folks actually have? They have acute myocardial injury. This is where there is a rise and fall in troponins that is not attributable to ischemia. We see this a lot actually, usually in patients with sepsis. It signifies end organ damage, but it's also seen in myocarditis, renal failure, and a slew of other things. Even a true type 2 end stemy where there isn't an occludus and there is just a mismatch of blood supply and demand, that must have the troponin elevation and one of those other criteria. It's easy to rule in or rule out. Do you have chest pain, sir? No. Look at the EKG. Okay, T waves fine, no Q waves, no left bundle, looks just like the old one. Let's get the echo. Hopefully it's not the weekend. Okay, all good. Acute myocardial injury, it is. One of those things not good? Maybe it's an MI. Maybe.

Annoyance 2: simvastatin

SPEAKER_00 10:00

Annoyance number two. Prescribing symvastatin. Symvastatin is one of the dumbest of all statins, rivaled possibly only by lovastatin, which has gone the way of bloodletting and trepanation. I don't know any self-respecting pharmacist who wouldn't laugh at you for prescribing symvostatin. Okay, that's a lot of hyperbole, but if you are familiar with the pharmacokinetics of it, you wouldn't disagree. From a drug metabolism standpoint, there are two types of statins, lipophilic and hydrophilic. Lipophilic statins are metabolized by the liver, by the cytochrome P450 system. I thought about naming my band cytochrome, but I don't play EDM. Hydrophilic statins have minimal to no metabolism in the liver and are instead excreted largely as is. It is the metabolism by the liver that is the issue. Symvostatin is lipophilic and undergoes extensive first-pass metabolism in the intestine and liver because only about 5% of it is bioavailable. Its metabolism is mediated by CYP3A4, which means it doesn't play well at all with other CYP3A4 inhibitors, of which there are many. Macrolides, calcium channel blockers, and antifungals are examples of more commonly used medications that you might run into trouble with. But a torvostatin is also metabolized by CYP3A4, you might be thinking. Well, probably you weren't thinking that, but yes it is, if you were. A torvostatin, however, is more bioavailable, 14%, meaning that less is metabolized by the liver, thus less issue. But still some. What's even better? Rosuvastatin. It undergoes minimal metabolism in the liver, so is not affected by SIP-mediated drug interactions. It is affected by transporter-mediated drug-drug interactions, but they tend to be things we don't use quite as commonly, like antivirals and warfarin. Although, if you are prescribing symvostatin, you are probably still prescribing warfarin. Alright, so symvostatin doesn't play well with other drugs. It also might play slightly worse with your muscle fibers. Yes, the whole statin-associated muscle symptom thing is pretty overblown, but it does happen in some people. And there is some evidence that symvostatin might be a worse actor than other statins. But this is at very high doses, 40 to 80 milligrams. Rosuvastatin has the lowest risk, likely. To be fair, symbostatin does not have any less benefit than other statins, it just comes with more baggage attached. I guess what I'm trying to say is why would you bother prescribing a dumber drug, symvostatin, when you have a smarter drug, rosuvastatin, or even a torvostatin, that is eager and ready to get in the game. Don't play your second string, man. Statins don't have feelings or overbearing parents who will yell at you for leaving them out. Go with the A team.

Annoyance 3: atenolol

SPEAKER_00 12:31

Annoyance 3. Prescribing a tenolol. So many sports references just now from a person who doesn't play sports. Bentelol. For the love of God, why? It's fallen out of favor at least. I don't know anyone under the age of 60 who prescribes it. And to be fair, it's not the worst at anything. It's just not the best at anything either. Super mediocre. The medication that gets the participation medal. Beta blockers in general are not recommended as first-line therapy for hypertension based on clinical trials that have shown they are inferior to other antihypertensives for the prevention of stroke, cardiovascular mortality, and all-cause mortality. 75% of these studies used attenolol, such that the only logical conclusion one could draw is that attenolol sucks. In fact, attenolol is better than placebo only for prevention of stroke. Yikes. And this is despite the fact that Atenolol lowers blood pressure to a similar extent as other antihypertensives. Maybe slightly less, but not a big difference. So why does it fail so massively? Well, it may be because beta blockers reduce pressure peripherally, but not centrally, so aortic pressure remains high. And central pressure is more associated with end organ damage, which makes sense because your organs are centrally located, although I don't know if that has anything to do with it. Okay, so not a great choice in hypertension. Not that other beta blockers are better choices for hypertension, or at least it's not entirely clear because mostly etenolol was studied and no one is interested in further studies on the topic at this point. But some other beta blockers have additional benefits. There is robust evidence that metoprolol succinate, carvatolol, and bisoprolol reduce hospitalizations and mortality and heart failure with reduced ejection fraction. Referred to the SIBIS2, Copernicus, and Merit HF trials. No great evidence exists for etenolol. There are a few smaller trials and animal studies that suggest it is definitely less effective. Others are more ambiguous, but because of the lack of clarity, we really shouldn't be using it with a reduced EF. It can be used in angina, but why bother? A lot of those patients have heart failures, so stick with metoprolol or carvatolol. Same with AFib. Even propranolol, a completely dirty drug with more side effects and sort of a schmuck, is better for migraine and tremor. Although carvatolol is kicking its ass in cirrhosis. So what explains the reason for etenolol'suckiness? I couldn't find much information on this, but one big difference is that etenolol does not cross the blood-brain barrier and other beta blockers do to some extent. It also has a shorter half-life, more similar to metoparolol tartrate, which does not have robust evidence of benefit in heart failure either, so possibly that's a factor, although it's just carvatolol that we know is better than metoparol tartrate. Okay, now I'm spinning. Fair to say, not all the beta blockers have been exhaustively tested against each other in all situations, and there is little motivation to do that since we already have data that a selection of beta blockers work pretty well, but not a tonalol.

Annoyance 4: the FeNa

SPEAKER_00 15:22

Annoyance number four, the FINA. The FINA dates back to 1976, the year of Jimmy Carter's election, the first Ebola outbreak, and the theatrical releases of the original The Omen and Carrie movies. Love me some blood-soaked sissy spasic. The FINA was first reported in JAMA by a Dr. Espinal who set out to develop a more objective way to differentiate between prereenal AKI and acute tubular necrosis. His study included 17 hospitalized patients with normal baseline renal function who had developed azotemia, that is, rising BUN and creatinine, and oliguria, or less than 20 mL per hour of urine output. So that is our population. He hypothesized that the differences in fraction of blood sodium excreted in the urine could help differentiate between groups. This idea is supported by the fact that when the kidneys are poorly perfused, as happens in a prerenal AKI, like with dehydration or cardiorenal syndrome, the renin angiotensin aldosterone system is activated to reabsorb sodium and water in the kidney as a countermeasure. By contrast, when the tubules are damaged, RAS is not activated and the kidneys struggle to reabsorb sodium because of injury. Dr. Espinell's conclusion was that for folks with prerenal AKI, the phenus should be less than 1%, and for ATN, it should be greater than 3%. There are some very important things to keep in mind about this study, though. First, all of the patients had normal renal function at baseline, no CKDers. Second, the participants were either prerenal or had ATN, no other suspected diagnoses. Third, they were all oliguric, making very little urine, less than 500cc per day. In the coming years, a number of studies would try to expand the eligible population for phenocalculation, but unfortunately, the results just became more muddied the more inclusive it got. When used on non-oliguric patients, values were often in the range between prerenal and ATN, so folks just started to use a cutoff of one, under for prerenal and over for intranal. This sacrificed the sensitivity and specificity of the test. Subsequent studies started including folks with CKD or on diuretics. A 2022 systematic review and meta-analysis by AbdelHafez et al. identified 19 studies on the subject published between 1976 and 2021. The sensitivity for the FENA to diagnose the cause of AKI ranged from 48 to 100%, and the specificity ranged from 39 to 100%. The test performed better in the earlier studies where patients were more carefully selected. And maybe it is still an okay test when used for oligarchic patients not on diuretics with normal baseline renal function who have either prerenal AKI or ATN and nothing else. In this very narrow situation, the test is 95% sensitive and 91% specific, but only in this very narrow situation. So let me mention a few of the abundant situations that can give you an erroneous result. Very low salt intake in the setting of ATN, or a very high salt intake in the setting of prerenal AKI, CKD in general, cirrhosis, glucosuria, including when using SGLT2 inhibitors, volume depletion that has led to ATN, getting normal saline through the IV, normal urine output despite the AKI, and on and on. So what's better? Well, the fractional excretion of urea is no better, possibly it's worse. And I'm not even going to go into it because it takes a long time to come back, so unless you are prepared to stare at your patient's failing kidneys for days before taking action, what's the point? Well, if phenot and effy urea are out, what's in? I typically would advocate for a good history taking combined with urine microscopy. Urine microscopy can give you a lot of information about a whole lot of different etiologies of AKI. And I wish urine microscopy were perfect on its own, but it's not perfect either. Biopsy is the gold standard, but we almost never do that. Let's consider the accuracy of microscopy compared to biopsy, though. If I'm dumping on the FENA, then I should fully understand what I'm advocating for. There was a relevant study of diagnosing ATN that compared the urinalysis findings and the FENA to histologic findings on biopsy. 49 patients undergoing kidney biopsy with previously calculated FENA and microscopy were included. Just over a third had CKD. No info about oliguri or meds they were on, though. Keep in mind that this was a very select group who went to biopsy. They weren't doing well and many needed some sort of renal replacement therapy, so not totally representative of the patient population at large. That said, among the 49 biopsied cases, the presence of muddy brown casts was only 78% sensitive for ATN. But the good news is that it was 100% specific, meaning that everyone who had those casts had ATN. But not all ATNers had muddy brown casts. A FENA greater than 1% was 90% sensitive for ATN, but only 71% specific, meaning that a fair amount of people with a FENA suggestive of ATN had a different diagnosis. In a larger sample that did not undergo biopsy, they found it was common to have a FENA less than 1% and high muddy brown cast burden. So prerenal fena with ATN microscopy, the opposite of what you would expect. This was the case in about 50% with a low FENA, indicating that the less than 1% value should never be used to exclude ATN. So can't exclude ATN for lack of casts or low FENA. I'm willing to bet that the sensitivity and specificity of a detailed history and urinalysis with microscopy is at least 90% for both. Not an evidence-based statement, just a wet thumb in the air to sense the direction of the wind kind of thing. And in the 10% of cases where I'm still not sure, well, given the variability and potentially poor performance of the FENA, that lab value isn't going to push me one way or another. Because it might be accurate, but it really might not be. Instead, I give a 500cc bolus and then recheck a creatinine to see if it helped.

Annoyance 5: checking folate levels

SPEAKER_00 21:24

Annoyance number five, checking folate levels. My argument against folate testing is based strictly on it being a crap lab test. Some of our patients are folate deficient. From an epidemiologic perspective, we're most often seeing folate deficiency in folks with diseases of malabsorption, like celiacs or from reduced intake, notably in alcohol and drug users, and socioeconomically disenfranchised older adults. Patients present with a megaloblastic anemia similar to B12 deficiency. My mantra has always been if you suspect a folate deficiency, just treat it. The argument has been made though that just Treating could mean ignoring the potentially serious clinical conditions that might be precipitating it. But my counterargument is that a folate deficiency typically isn't occurring in isolation unless you have a genetic condition, which is rare, so check the vitamins with more reliable assays. Serum folate is not very useful because it's more reflective of transient folate deficiency and can be low in patients with poor intake for just a few days. Now many providers say we should be checking RBC folate levels instead, as it reflects folate levels over several months. This test is so fraught though that many labs have removed it from their repertoire altogether. Folate must be extracted from the cells, it is unstable once extracted, and then requires that folate with polyglutamate chains be converted to monoglutamates. Methodology can vary a lot between labs, such that results from one lab can't be compared to results from another lab. In any case, the College of American Pathologists recommends checking serum folate, not RBC folate. I recommend just giving vitamins. Or a box of Twinkies because they're fortified.

Annoyance 6: checking serum ammonia levels

SPEAKER_00 23:01

Annoyance number six: Serum ammonia levels. Today I am going to make a bold move and argue that we should never, ever, ever order serum ammonia levels in the setting of cirrhosis. There. I said it. Mic drop. Okay, okay, I can tell you want some supporting data. Happy to oblige. Hyperommonemia develops in cirrhosis for several reasons. The most obvious of which is that the hepatocytes are supposed to metabolize ammonia in the urea cycle, but when the hepatocytes are crapping out, that doesn't happen. There is also evidence that changes in the microbiome can lead to overproduction of ammonia via bacteria. And finally, portal hypertension leads to portosystemic shunting, meaning that some of the blood that is supposed to go through the liver before returning to systemic circulation just goes there directly before processing. But checking ammonia levels to diagnose hepatic encephalopathy is something we absolutely should not be doing. Issue number one, testing the serum for ammonia is problematic. Arterial ammonia is more accurate than venous samples, but we're probably not going to be getting that. Then samples really should be put on ice immediately, as there may be deamination in samples left at room temperature for any extended time. That is, more ammonia is produced in the sample while it just sits there. Great. Issue number two, ammonia isn't the only cause of hepatic encephalopathy. There is systemic inflammation and increased oxidative stress and cirrhosis, which disrupts the integrity of the blood-brain barrier, leading to neuroinflammation. Increased circulating bile acids, electrolyte imbalances, and altered brain metabolism also play a role. So ammonia is just one piece of the puzzle that we'd be measuring. Issue number three. Ammonia levels are not associated with presence of or degree of hepatic encephalopathy. Because of this, the AASLD and the EASL recommend diagnosing and managing hepatic encephalopathy based on clinical and not laboratory indicators. My favorite paper on this subject was published in 2024 by Bajaj et al. in Clinical Gastroenterology and Hepatology. Serum ammonia levels do not correlate with overt hepatic encephalopathy severity in hospitalized patients with cirrhosis. The title kind of says it all. This had been a randomized control trial to compare different formulations of rifaximin with lactulose, but then COVID exploded and the trial was stopped along with life itself. They were able to cleverly repurpose the data from 44 participants who had serum ammonia levels ordered on day one. The trial population was all patients with cirrhosis, median age 63, about half women. Their first finding was that there was no association between day one ammonia levels and severity of encephalopathy as determined by the hepatic encephalopathy grading instrument. I'm more familiar with the West Haven criteria, but they seem roughly similar. Some with mild encephalopathy had very, very high levels, and some with more severe symptoms had much lower levels. There was also no relationship between ammonia levels and severity of liver disease as determined by MELDS score. And finally, there was no relationship between time to resolution of encephalopathy and ammonia levels. So levels didn't correlate with severity of liver disease, severity of encephalopathy, or course of illness. So worthless. The associated graphs in the paper are impressively unimpressive. Now I can bike drop. Thank you everyone for tuning in. I leave you all now to embark on your journey of improved terminology, deprescribing, and thoughtful lab ordering. See you next time. Thank you.