Time Stamps

  • 02:59 Pearl 1 – Types of Corticosteroids
  • 14:31 Pearl 2 – Side Effects of Steroids
  • 21:15 Pearl 3 – Prophylaxis 
  • 27:32 Pearl 4 – Steroid Weaning 
  • 33:38 Pearl 5 – Steroid Weaning Limitations 

CME-MOC

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Show Notes

Pearl 1:  How do you choose which steroid to order?

  • Order steroids based on a spectrum that uses three guiding principles!
    • Three guiding principles:
      • Glucocorticoid (anti-inflammatory) activity
      • Mineralocorticoid activity
      • Potency & half-life
    • Steroid spectrum:
      • Hydrocortisone → Prednisone → Methylprednisolone → Dexamethasone
      • Mnemonic: High Powered MD
  • Glucocorticoid (anti-inflammatory/immunosuppressive) activity:
    • Activity increases along spectrum
    • Example: Dexamethasone has the HIGHEST glucocorticoid activity (our “bazooka gun”). Used in emergencies to decrease inflammation (cord compression or brain metastasis).
  • Mineralocorticoid activity:
    • Activity decreases along spectrum
    • Increases fluid retention and blood pressure
    • Example: Hydrocortisone has relatively more mineralocorticoid activity. Used in septic shock.
    • Note: Fludrocortisone is an exception!
      • HIGHEST mineralocorticoid activity
      • Mild glucocorticoid activity
  • Potency & half-life:
    • Activity increases along spectrum
    • Example: Hydrocortisone has LOWER potency & half-life. Used in adrenal insufficiency (more closely mimics natural cortisol production).
    • TIP: Lower potency & half-life are preferred
      • Less hypothalamus pituitary adrenal (HPA) axis suppression
      • Reduced risk of adrenal insufficiency
  • Conversion Factors:
    • 1 mg of dexamethasone =
      • 4 mg of methylprednisolone
      • 5 mg of prednisone
      • 20 mg of hydrocortisone
    • TIP: To estimate steroids in prednisone equivalents:
      • Multiply by 5 if starting with dexamethasone
      •  Divide by 5 if starting  with hydrocortisone

Pearl 2: What have studies shown in terms of dose and duration for worrisome complications? 

Pearl 3: What types of prophylaxis should be started in patients on steroids and when? 

Pearl 4: In which patients should we wean steroids vs. stop abruptly and how should we do so? 

  • Weaning steroids:
    • When? No clear guideline
      •  Consider duration of steroid of use when deciding to taper
        • Frequent, short steroid courses
        • Long courses of steroids
          • If the patient is on high dose steroids
            • Wean to lower levels rapidly
            • Slow taper at 20 mg prednisone to prevent withdrawal
          • Can transition to hydrocortisone
            • It’s half-life is similar to physiologic cortisol production
            • It has a shorter half life, which the body’s HPA axis time to “wake up” and encourages endogenous steroid production (unlike consistent HPA suppression with longer acting steroids)
  • Abruptly stop steroids:
    • When? No clear guideline
      • Consider duration of steroid use when deciding to abruptly stop
        • Can feel comfortable stopped if < 7 – 14 days of steroid course
        • Infrequent, short steroid course
          • Example: Patient with infrequent asthma OR a 2-3 day course of stress dose steroids

Pearl 5: What factors limit steroid weaning?

  • Recurrence of the disease that was being treated by steroids
  • When should we consider adrenal insufficiency in a wean?
    • Average daily cortisol production is equivalent to 10-15 mg of hydrocortisone or prednisone 2.5-3.5 mg
      • Low risk if <2 weeks
      • Moderate risk if taking equivalent of 5 mg of prednisone for >2-4 weeks
      • Higher risk if on 5 mg of prednisone equivalent for >4 weeks
  • Steroid Withdrawal Syndrome:
    • Can affect up to 80% of patients
    • Fatigue, malaise, anxiety, and myalgia
    • Not associated with adrenal insufficiency
  • Some patients may be hesitant to transition to biologics if they have been on steroids for a while and it works for them!
    • This can be an opportunity to counsel and partner with your patient!

Transcript

Dr. Beth Wallace: Do you know any other drug, any other drug on the market? I mean, if you tried to put steroids on the market right now, if you tried to get steroids past the FDA, there’s no way, right? There’s way too many side effects to, to have steroids be FDA approved for anything. And yet they’re FDA approved for like every autoimmune condition. They’re FDA approved for COPD. You know, there’s so many different things that they’re FDA approved for just because they’re grandfathered in.

Dr. Shreya Trivedi: That was Dr. Beth Wallace, a Rheumatologist at the University of Michigan. And today we are talking all things corticosteroids aka steroids!

Dr. Michael Weintraub: Glucocorticoids are a double edged sword or I don’t know if you could make it a triple edge. There’s a lot of benefits, but also really salient chronic and acute issues with steroids.

Dr. Shreya Trivedi: And that was Dr. Michael Weintraub, an Endocrinologist at NYU. I am Dr. Shreya Trivedi and welcome to the CORE IM 5 pearls podcast, bringing you high-yield evidence based pearls. And this episode on steroids. Really wouldn’t have been possible without Dr. Casey Kim!

Dr. Casey Kim: You flatter me, Shreya! But hi, all! I’m Casey, I’m a second year Internal Medicine resident at Beth Israel Deaconess Medical Center. I really was excited to dig into this topic because I just felt like I was using steroids every day, but not really understanding them. I had so many questions about when to start, what to start, when to stop, how to do so. Most of the time, it felt like I was just starting and stopping steroids at random. 

Dr. Shreya Trivedi: Ah, same. We’ve all been there!

Dr. Casey Kim: So, you know, with that, let’s get started with our five questions on steroids. Make sure to test yourself by pausing after each of the five questions. 

Dr. Shreya Trivedi: And remember the more you test yourself, the deeper your learning gains

Dr. Casey Kim: Pearl 1 – Types of Corticosteroids 

Dr. Shreya Trivedi: What are 3 guiding principles that can help us choose between the different types of steroids?

Dr. Casey Kim: Pearl 2 – Side Effects of Steroids 

Dr. Shreya Trivedi: What have studies shown in terms of dose and duration for worrisome complications? 

Dr. Casey Kim: Pearl 3 – Prophylaxis 

Dr. Shreya Trivedi: What types of prophylaxis should be started in patients on steroids and when? 

Dr. Casey Kim: Pearl 4 – Steroid Weaning 

Dr. Shreya Trivedi: In which patients should we wean steroids vs. stop abruptly, and how should we do so? 

Dr. Casey Kim: Pearl 5 – Steroid Weaning Limitations 

Dr. Shreya Trivedi: What factors limit steroid weaning?

Dr. Casey Kim: There are so many different corticosteroid formulations – and like I was just mentioning, how should we think about which one to start and why?

Dr. Shreya Trivedi: This is a great question to start off with. I think for a lot of us we just pick up patterns along the way “oh this is the one I give for COPD” and “this is the one is for stress dose steroids” and now with COVID, “this is the one I give for COVID.”

Dr. Casey Kim: Yeah, I definitely have those associations in my mind too, and I wanted to see if we could get a deeper understanding of why we choose one vs the other, especially for the 5 big ones that I see the most frequently: hydrocortisone, fludrocortisone, methylprednisolone, prednisone, and dexamethasone.

Dr. Afreen Shariff: So when you look at steroids they don’t come in the same shapes and sizes. They’re steroids, yes, but I don’t say they’re siblings, they’re cousins are the same family because they really have different effects. So really picking and matching your steroid to what effect you want to get to in the end is really critical. And understanding where your steroid falls on that spectrum really helps you make that decision.

Dr. Shreya Trivedi: That was Dr. Afreen Shariff, an endocrinologist at Duke, one of our experts (and yes brace yourself there will be 4 from different specialties that we interviewed because steroids are used by so many different people). So when we sat down with experts, we came away with three general guiding principles.  

Dr. Casey Kim: Speaking of which, first two principles have to do with the amount of glucocorticoid activity and amount of mineralocorticoid activity. Remember our adrenals produce endogenous steroids that have a range of glucocorticoids and mineralocorticoid activity.

Dr. Shreya Trivedi: Casey, just to let make sure we are on the same page here, what do we mean by that first principle – glucocorticoid activity. 

Dr. Casey Kim: So, glucocorticoids have systemic effects in our metabolism, and do lots of things but for our purposes, we’ll simplify the glucocorticoid activity as to how much have anti-inflammatory activity a steroid has.

Dr. Shreya Trivedi: And then what do we mean by that second principle for determining which steroid to choose, what exactly do we mean by mineralocorticoid activity.

Dr. Casey Kim: So if we simplify mineralocorticoid activity, basically what we’re talking about is that the more mineralocorticoid activity a steroid has, the more salt and water retention by the kidneys, so this often leads to higher blood pressure and fluid accumulation. 

Dr. Shreya Trivedi: Great! And then as a rule of thumb, we can think of glucocorticoid activity and mineralocorticoid activity on opposite spectrums. So, the more glucocorticoid activity a steroid has, generally, the less mineralocorticoid activity that steroid has. And then on the flip side, the more mineralocorticoid activity a steroid has, relatively, the less anti-inflammatory or glucocorticoid activity.

Dr. Afreen Shariff: So, if you look at it as a spectrum and you look at it moving from say, maximum glucocorticoid effect to say maximum mineralcorticoid effect, you start seeing that dexamethasone is really heavy on that glucocorticoid spectrum where you don’t have a lot of mineralocorticoid activity. So if you want to get most bang for your buck with kind of the fire extinguisher effect of steroids, you really want to go with the bazooka steroid, which is kind of the dexamethasone, right? And somewhere in between is your prednisone, your methylprednisolone. Those come somewhere right in between where they have more glucocorticoid but some mineralocorticoid activity. And then you move forward with that spectrum and you’re going further down, and then you see that you’re hitting more of the mineralcorticoid activity, and then you hit your pure mineralocorticoid, which is fludcortisone, and hydrocortisone is somewhere in between your prednisone and fludrocortisone.

Dr. Casey Kim: You know, Shreya, I actually made a mnemonic to help us remember the spectrum and the strength of steroids for each of our 3 principles!

Dr. Shreya Trivedi: Okay, I love me some mnemonics. I would love something to help me remember the order versus just going off gestalt of how strong I think something is! 

Dr. Casey Kim: Okay, so the mnemonic is something I strive towards being. It’s a “High Powered MD!” Each letter stands for a different corticosteroid, starting with hydrocortisone, going to prednisone, then methylprednisolone, and then dexamethasone. I did leave fludrocortisone out, but that’s because it doesn’t always fit neatly into this spectrum. 

Dr. Shreya Trivedi: Oh okay, nice! Hopefully, we’ll have this all in an infographic as a reference. Okay, so if we take that High Powered MD pneumonic, if we think about the glucocorticoid or anti-inflammatory effect, it increases moving along that spectrum. So if we start with hydrocortisone, that H, it has the least glucocorticoid activity. And then to dexamethasone, on the other end, has the most amount glucocorticoid, anti-inflammatory activity. 

Dr. Casey Kim: So this makes a lot of sense when we think of clinical situation when we reach for dexamethasone. We use it in emergencies, like spinal cord compression or brain metastases. You want the strongest glucocorticoid and anti-inflammatory effect possible. So, there you go – dex!

Dr. Shreya Trivedi: Yep! Like Dr. Shariff was saying. Dex is that bazooka gun, anti-inflammation fire-extinguisher. And also explains why we reach for dex in acute respiratory distress syndrome, ARDS in the ICU. This is largely an inflammatory lung injury.

Dr. Beth Wallace: The dexamethasone is the drug of choice for lung information inflammation. So ARDS, um, especially in, uh, pneumonia or sepsis, and it’s the DEXA ARDS trial and then COVID with pulmonary involvement, the RECOVERY trial, both, both of those use dexamethasone.

Dr. Shreya Trivedi: And in addition to that anti-inflammatory bit, the bonus is that dexamethasone essentially has no mineralocorticoid activity. So it’s good for those patients who are are sensitive in terms sodium retention, fluid balance, and now that I think about it, I guess a  similar thinking applies to why for COPD or asthma, we often reach for methylpred or prednisone on the floors or outpatient

Dr. Casey Kim: Right! Because oftentimes these patients may have concurrent heart failure and, you know, we don’t want to give them another reason to be short of breath with fluid retention from steroids. 

Dr. Shreya Trivedi: Exactly, exactly, so prednisone and methylpred are thought to have more of that glucocorticoid anti-inflammatory activity and less of that mineralocorticoid activity.

Dr. Casey Kim: Speaking of mineralocorticoid activity, just  as a quick recap of our High Powered MD mnemonic, mineralocorticoid activity decreases along this spectrum, so the H in High Powered MD is hydrocortisone which has the strong mineralocorticoid activity, with prednisone and methylprednisolone in the middle and dexamethasone, our champion glucocorticoid, having no mineralocorticoid activity. 

Dr. Shreya Trivedi: Whomp, whomp! But also good, in some cases. So if we think of when we reach for hydrocortisone, which has relatively more mineralocorticoid activity, it’s going to be in septic shock or stress dose steroids, say in someone with adrenal insufficiency. But, yeah, I can see now because it has relatively higher mineralocorticoid activity, it’s going to keep blood pressure up in that patients with septic shock and adrenal insufficiency. But now that I’m thinking about this more, sometimes, I have seem people reach for fludrocortisone in these cases, too, but you mentioned fludrocortisone is the exception to the High Powered MD? So, how should we think of fludrocortisone?

Dr. Casey Kim: Yep! Fludrocortisone is that one cousin that doesn’t follow the family rule of thumb.

Dr. Shreya Trivedi: Always have that one!

Dr. Casey Kim: I know, there’s always one, right! The thing to remember is that has the strongest mineralocorticoid activity but it also has mild glucocorticoid activity. And by strongest mineralocorticoid, I mean it is off the charts compared to the other steroids, in terms of relative strength of mineralocorticoid activity.

Dr. Shreya Trivedi: If it is off the charts, then why don’t we reach for fludrocortisone in septic shock? It has the most mineralocorticoid activity – why are we reaching for hydrocortisone? 

Dr. Casey Kim: So the thought is that hydrocortisone has sufficient mineralocorticoid activity, so it does the job, so to say. But it’s a hot topic and an active area of research, with trials comparing hydrocortisone versus fludrocortisone, or hydrocortisone plus fludrocortisone in the ICU setting around septic shock. 

Dr. Shreya Trivedi: Nice! So we will have front row seats as the plot thickens! Okay, this has been really great, Casey, I’m like smiling here just cementing each of these steroids and the amount of glucocorticoid and mineralocorticoid activity each has. And really help build that strong reasoning for why might be using a steroid in one case versus the other. 

Dr. Casey Kim: Yep! But let’s take it up a notch with our  last principle: the steroid’s half life and potency. 

Dr. Shreya Trivedi: Ah okay, yeah! So thankfully the half-life and potencies, for the most part, does track together and if we go back that High Powered MD spectrum. On the left, hydrocortisone having the shortest half life, the lowest potency, and if we move up, on the other end of the spectrum, dexamethasone has the longest half life and highest potency.

Dr. Casey Kim: When I first heard this principle, I got really curious, you know, how potency or half-life matter? Can’t you just use equivalent doses among the different types of steroids?

Dr. Michael Weintraub: So if someone’s on dexamethasone with a really high biological half-life of 36 to 54 hours, that’s basically suppressing our own hypothalamic pituitary adrenal axis 24-7 versus something like hydrocortisone, where we might have our HPA axis might have time to kick in, and produce its known own endogenous cortisol and not kind of atrophy over time.

Dr. Casey Kim: Oh! So long acting steroids like dex suppress the HPA axis more, so that’s why we actually reach short acting steroid like hydrocortisone in adrenal insufficiency, because that shorter half life mimics natural cortisol production multiple times a day.

Dr. Beth Wallace: For one, it’s a direct physiologic analog. Your body makes hydrocortisone and hydrocortisone is available as a drug that you can buy. So it’s exactly what your body makes. It’s also short acting, so you can give it two or three times a day to mimic the physiologic secretion. Or if someone needs stress dose steroids, uh, for instance, someone with adrenal insufficiency who is sick or having surgery, um, you can dose, uh, hydrocortisone even more often than that. 

Dr. Shreya Trivedi: And we’ll talk about adrenal insufficiency more in Pearl 5. There’s actually a whole Core IM episode on it too, but in general, we should pick steroids with lowest potency and half-life that will work for the chosen indication to minimize suppression of the HPA axis and minimize the risk of adrenal insufficiency. 

Dr. Casey Kim: Speaking of potency, Jeff Fish, an ICU pharmacist at the University of Wisconsin Health Systems, gave us his rule of thumb for converting doses between the steroids.

Dr. Jeffrey Fish: We always talk about the conversion factor between them, where dexamethasone one milligram is equal to four milligrams of methylpred, it’s five milligrams of prednisone, it’s equal to 20 of hydrocort. So if you do have to convert back and forth between them to use that conversion.

Dr. Casey Kim: To make this easier, I like to think of steroids in terms of prednisone equivalents, so I’m either multiplying or dividing by 5. So if I have dexamethasone, I’ll multiply by 5 or with hydrocortisone I’ll divide by 5 to get a ballpark prednisone equivalent dose. 

Dr. Shreya Trivedi: Ah, Casey you are so helpful with these rules of thumbs and and these mnemonics – love it! 

Dr. Casey Kim: Shreya, I try! You just gotta simplify! Right?

Dr. Shreya Trivedi: I know! Said like a true educator, that likes to decrease cognitive load. Alright, so let me try to take a stab at the takeaways! Big picture, we are learning that not all steroids have the same amount of anti-inflammatory and mineralocorticoid effects. And if you think of steroids on a spectrum, the strongest glucocorticoids, such as dexamethasone has the lowest mineralocorticoid activity and vice versa with hydrocortisone having relatively more mineralocorticoid activity and relatively less anti-inflammatory activity. With the exception of fludrocortisone, its that cousin that doesn’t really fit as well, unfortunately, but fludrocortisone blows all the other steroids out of the water with how much relative mineralocorticoid activity it has.  

Dr. Casey Kim: And then the last factors, is the half life and potency. With dex having the longest half life and potency and then following a similar pattern, hydrocortisone, one the other end, having relatively short half life and potency.

Dr. Casey Kim: So, now we know what type of steroid to start a patient on, let’s dive a bit more into side effects. 

Dr. Shreya Trivedi: Honestly, what side effects don’t steroids cause? You list them, and steroids probably cause them!

Dr. Michael Weintraub: So weight gain, bone demoralization, osteoporosis is a real thing. Real problem. Blood sugars, someone who has type two diabetes placed on prednisone 20 milligrams twice daily, prednisone, their blood sugar’s going to go through the roof. Increased infection. Dyslipidemia. Are all real issues that chronically over time do increase our risk for heart attack, strokes, metabolic disease.

Dr. Beth Wallace: I mean, even just AVN alone, right? If you’re like up to 30% of people who take this drug can have, you know, just rotting of their hip, it can just disintegrate. Like that’s unacceptable, that’s really unacceptable. But if we didn’t do it, if we didn’t pulse people who were, you know, in the ICU intubated with pulmonary renal syndrome, they would die. So it’s, it’s a trade off.

Dr. Shreya Trivedi: Wow, 30% AVN, avascular necrosis? That’s is so high.

Dr. Casey Kim: I know, I know. I thought it was really high too. So, I looked it up and the range is variable, but it’s anywhere from 4-40% reported in studies of glucocorticoid associated vascular necrosis in various conditions.

Dr. Shreya Trivedi: Yeah, and that brings up one question that comes to mind. You know, what’s the rate and frequency with which some of these side effects occur? You know, is there a certain dose or duration of steroids that really puts you at risk? And if so, maybe that can also help us counsel kind of our patients when it comes to steroid bursts and risks with that, too? 

Dr. Casey Kim: Yeah, so it looks like most cases of AVN started around 33 months, so over a year, but there have been several cases of AVN that were noted after only 3 months. The earliest recognition was only after, maybe, a little over more than a month of 16 mg/day of oral methylprednisolone or a cumulative dose of about 570 mg of methylpred.

Dr. Shreya Trivedi: Oh, wow! And I guess for reference, a single dose pack of methylprednisolone, those steroid bursts, is typically 24 mg/day and contains about 84 mg total over only 6 days. 

Dr. Casey Kim: So you know, on its own, it’s not really enough to cause AVN, but it does make me wonder at how much these dose packs could add up for patients. Especially those who need repeat steroid courses over a short period of time. 

Dr. Shreya Trivedi: Something I always wonder about with steroid courses, is what’s the risk of infection? Right? You know, sometimes I’ve seen patients who come in with infections after short courses of steroids for COPD or asthma, I’ve never been sure if I should think of these patients as immunocompromised or not.

Dr. Beth Wallace: Yeah, so this is another question where the field is rapidly changing. So if you look back five or 10 years, most people would’ve said that long term use of five know, five milligrams or less, or even really seven and a half milligrams or less wasn’t really associated with the clinically significant, uh, risk of infection. And most people also would’ve said that bursts. So the, you know, short tapering courses we use for things like gout or RA flares or COPD flares or asthma, were also pretty low risk. But there’s been several recent large, um, retrospective cohort studies done using claims data that suggest this isn’t true. So the, the most recent one was Tsung-Cheih Yao, that was published in the Annals of Internal Medicine in 2020. And this was a retrospective cohort study looking at bursts of less than 14 days using Taiwanese claims data.” And this, their, their claims database captures basically the entire population of Taiwan. You know, all of their claims, all of their visits, all of their prescriptions, etc. And they found that over a two year period, about a quarter of the population got steroids. And these were mostly healthy young people and they were mostly getting them for things like URIs, laryngitis, bronchitis, so the equivalent of, you know, dose packs that would get prescribed at urgent care here in the US. And they found significantly increased rates of three pretty serious outcomes. GI bleeds, sepsis, and heart failure. And these absolute risk differences were very small. They were on the order of, uh, 0.1 to 10, um, per a thousand person years, but 40,000 GI bleeds, 400 cases of sepsis, and 4,000 cases of heart failure were directly attributable to these bursts over this two year period.

Dr. Shreya Trivedi: Wow, I don’t really think about the impact on individual patients who are on these short steroid courses, but I was surprised that on a population scale, it looks like even short bursts can increase your risk of pretty significant side effects.

Dr. Casey Kim: And Shreya, what i found interesting was that this even played out for low doses of steroids as well, too. I remember Dr. Wallace told us about another study that showed higher rates of infection looking at claim data of patients with rheumatoid arthritis. And some of these patients were only on five milligrams of prednisone or less. And what I really loved was hearing how Dr. Wallace conceptualizes the infection risk on steroids.

Dr. Beth Wallace: So taking three or four milligrams of prednisone is comparable to taking a TNF inhibitor in terms of the increase in infectious risk. So that’s not, that’s not nothing, it’s not huge, but it’s not nothing. So the best answer based on the data we have right now, um, to this question is any dose for any duration is probably somewhat immunosuppressive, but the risk is dose dependent, just like all the other risks of steroids. So the lower the better, but any, there’s no safe dose essentially from an infection standpoint.

Dr. Casey Kim: I think she also had the best summary when it comes to risk while on steroids. 

Dr. Beth Wallace: The kind of way the kind of way that I recommend looking at steroids is looking at them from a stewardship perspective. So sort of like we look at opiates or antibiotics, um, we, we previously, and even when I trained, right, when I trained in residency, we prescribe short courses of steroids for lots of things. Oh, sinusitis, we’ll give you some steroids that’ll make you feel better, you know, low back pain, we’ll give you some steroids because we thought they were safe. We thought if this is a young, healthy person, we’re giving them, you know, seven days, 10 days of steroids, this isn’t gonna cause any problems. But it’s clear now that that’s not true. It, it’s, the risks are small, but they’re real. And these are avoidable events. So just as you wouldn’t prescribe antibiotics for a viral infection, don’t prescribe steroids when there’s not a clear indication for their use. Hashtag steroid stewardship is a hashtag I have tried to insert into Twitter into my twitterverse, um, that I hope we can.

Dr. Shreya Trivedi: I like the challenge. We can get that trending!

Dr. Beth Wallace: Do it! So excited!

Dr. Shreya Trivedi: Happy, a budding tutorial list. And so, um, we’ll see what we can do when we publish this episode. 

Dr. Casey Kim: Wow! So I knew that steroids caused a lot of different side effects, but for the patients that do have to be on steroids, we can mitigate some of these bad side effects a little bit with prophylaxis, right? 

Dr. Shreya Trivedi: Yeah! You know we’ve got PJP prophylaxis, GI ulcer prophylaxis, osteoporosis prophylaxis. So much, and also, not enough, probably!

Dr. Casey Kim: Yeah, all the prophylaxis, but let’s start with prophylaxis for PJP aka pneumocystis jiroveci pneumonia! 

Dr. Shreya Trivedi: Oh, hats off, that was probably a mouthful! So yeah, when do we start TMP-SMX or as second line primaquine plus clindamycin, or atovaquone to prevent that PJP?

Dr. Casey Kim: That was also a mouthful! But the general thought is to start PJP prophylaxis when a patient is on 20 mg of prednisone equivalent corticosteroids for greater than 1 month, which is what our experts endorsed as well as guidelines from National Comprehensive Cancer Network and American Thoracic Society.

Dr. Shreya Trivedi: Okau, so 1 month or more of 20 mg of prednisone equivalent, great! One thing that surprised me was just think about the indication of that steroid use in the first place and how that may play into how we think about the risk of PJP and starting prophylaxis. 

Dr. Beth Wallace: Within rheumatology, you know, speaking again from sort of anecdotal clinical experience, um, the threshold also depends on the indication. So for instance, patients with ANCA vasculitis just get PJP  more often and are prophylaxis at much lower doses than people with lupus. People with lupus, they can be on, you know, 60, 50, 40 milligrams of prednisone for months and they don’t get PJP. And I had a patient with ANCA vasculitis who, um, she was on atovaquone and her atovaquone prior auth expired and she couldn’t get it renewed. But there was a, a, you know, period of a week or two where she didn’t have any prophylaxis and she got PJP in that little tiny period of time. So they’re just more prone to it. So it sort of depends on, you know, what on steroids for.

Dr. Casey Kim: Wow! It’s humbling that just 1 week of prior auth nonsense made such a difference.

Dr. Shreya Trivedi: Yeah, ugh!

Dr. Casey Kim: And also so interesting to think about how these different steroid and disease state interactions might change how you think about various risks. 

Dr. Shreya Trivedi: Yeah, definitely a lot of nuance, right, and I think one of the reasons why having guidelines on things like steroid prophylaxis can be a challenge, right, there’s such a variety of conditions that patients are on steroids for and a lot of different of side effects, too.  

Dr. Casey Kim: Speaking of different other steroid side effects, the one of the other ones I’ve seen are steroid-induced GI side effects or ulcer side effects. You know, I’ve definitely heard of starting a PPI for patients on steroids, but feel like I’ve seen it pretty variably in practice. 

Dr. Shreya Trivedi: Yeah, there is some controversy over whether or not steroids in and of themselves are associated with ulcers and GI bleeding, but at least from studies we’ve seen, the risk of ulcers increases by four fold whenever a patient is on steroids plus an NSAID. So some effects, like steroid plus blood thinner can really synergize based on a patient. 

Dr. Beth Wallace: Um, from a GI standpoint, I do use guidelines for this. So anyone who is taking an NSAID plus prednisone, I prophylaxis. Anyone with an ulcer history or who has, who has GI side effects from steroids. So if they get on steroids and they say, “Oh, I’m having a lot of GERD, I think it’s from the steroids,” I prophylaxis that person, um, anyone on blood thinners, uh, of any kind. So DOACs, warfarin, any of that. Um, and then age sort of factors in so that there’s no specific cutoff, but the older someone is the more I sort of think about it. 

Dr. Casey Kim: So to recap, anyone on steroids  who is also on an NSAID or a blood thinner, or who has a history of ulcers and GI side effects, should be GI prophylaxis if they’re on steroids, whether that be a PPI or an H2 blocker.

Dr. Shreya Trivedi: Yeah, and last but not least, let’s talk about calcium and vitamin D. I feel like all patients on chronic steroids are on some calcium and vitamin D.

Dr. Casey Kim: Yeah and just to be explicit, the hope with the calcium and vitamin D is to prevent glucocorticoid induced osteoporosis.  

Dr. Shreya Trivedi: And if we look at the pathophys, steroids induce negative calcium balance – steroids both decrease intestinal absorption and increase the Ca excretion in the urine. So basically steroids decrease how much Ca is going in and increasing how much is going out.

Dr. Casey Kim: And thats why steroid induced osteoporosis is very common. The risk of fractures increases even on 2.5 to 7.5 mg of prednisone daily and that’s just the first 1-3 months. 

Dr. Shreya Trivedi: Yeah, and that’s why for any patient who is on a steroid for any dose greater than 3 months, The American College of Rheumatology (ACR) Task Force recommends getting enough calcium and vitamin D whether it be their diet or supplements –  but, Casey, I’m curious is the calcium and vitamin D clinically helpful?

Dr. Casey Kim: So it’s kind of mixed, we do see improved bone density but no difference in incidence of non-traumatic fractures.  

Dr. Shreya Trivedi: Ah, I was thinking that would be the case. But what about bisphosphonates? Do they help more in steroid induced osteoporosis?

Dr. Casey Kim: Yeah! So bisphosphonates have actually been shown to have a little bit more benefit. They help with with lumbar spine and femoral neck bone mineral density and as a bonus, have shown to reduced risk of new vertebral fractures, as well. 

Dr. Shreya Trivedi: Okay, that’s good to know. So maybe, should all patients who are on steroids take bisphosphonates to reduce their fracture risk? 

Dr. Casey Kim: The off the bat people who should be on bisphosphonates are your 40 year olds or older on high dose glucocorticoids, which is initial dose prednisone ≥ 30 mg/day or cumulative dose ≥ 5 gm in 1 year [the American College of Rheumatology]. 

Dr. Shreya Trivedi: And then I’m guessing everyone else use a FRAX score aka Fracture Risk Assessment Tool to helps us stratify the risk of fracture over ten years?

Dr. Casey Kim: Right! So anyone on prednisone ≥ 2.5mg/day for > 3 months should also get a FRAX score to see their risk. 

Dr. Shreya Trivedi: Yeah awesome! So if I can summarize this pearl, and maybe I can try to reinforce the teaching points from a timeline or duration of steroids perspective, so on day 1, if my patient is on on steroid and their on an NSAID, a blood thinner or has a history of ulcers or GI symptoms, then you can go ahead and get started on GI prophylaxis. At the 1 month mark of being on steroids, we could consider starting PJP prophylaxis if they are on on equivalent of prednisone 20 mg or more. And then at the 3 month mark, the recommendation is all patients should be on vitamin D, Calcium, and should have a FRAX score done to see if bisphosphonates may be indicated.

Dr. Casey Kim: Ok, so while we do love preventing some of those side effects with prophylaxis, what about just stopping steroids altogether?

Dr. Shreya Trivedi: Let’s do it Casey! Stop the steroids and start the wean! 

Dr. Casey Kim: Haha, except you just brought up my one weakness – steroid tapers.

Dr. Shreya Trivedi: Oh, yes, yes, yes! Aren’t they tough ones!

Dr. Casey Kim: Yeah, but really, it felt like a toss up whether or not we should stop steroids immediately or wean them, and then, I was never sure how long to make the taper either. 

Dr. Shreya Trivedi: Sounds like the million dollar question! 

Dr. Afreen Shariff: Everyone has a different way of doing this. I always say you ask five different endocrinologists, you’re going to get 10 different answers in how they want to do steroid tapers. It’s really comes down to the art of medicine. There’s no perfect way of doing this. There’s no design, set way of doing this.

Dr. Casey Kim: When we did sit down and talk to our experts and reviewers who are pharmacists, endocrinologists, rheumatologists, and pulmonologists, one of the biggest factors in determining whether or not a steroid should be tapered came down to duration of steroid use. 

Dr. Jeffrey Fish: I always have used, if they’re on it for seven days or less that you can just stop it, cold. If they’re on it for more than 14, then you should wean it. If they’re on from seven to 14 then it kind of depends on the dose and what you’re using it for. Most trials just stop it after the treatment course. And even the one that I was surprised with is the DXA ARDS trial, where they gave that 20 milligrams of dexamethasone for five days and then the 10 milligrams for five days. They just stopped it after. So 10 days of very high dose dexamethasone, they just stopped it.

Dr. Casey Kim: So to give context, if you use my rule of thumb of multiplying by 5, 20 mg of dexamethasone is roughly 100mg of prednisone and 10mg of dexamethasone daily is roughly 50mg of prednisone, which is a wapping dose!

Dr. Shreya Trivedi: Yeah, sometimes you don’t realize that when you’re just ordering it, so, yeah, I appreciate that context! I think the other thing that surprised me, Casey, was hearing the impact of multiple short bursts of steroids over time. 

Dr. Michael Weintraub: So we all had that patient who has been treated with five courses of prednisone or medrol dose packs for their COPD exacerbations or they’re getting steroids for chemo to as an anti-emetic. There have been a number of studies that have looked at these populations of people against small N, but if we have, say there was a one study of about 300 patients who were COPD patients who were given prednisolone for short courses like a couple weeks, but they were given for frequent courses, about 10% developed adrenaline’s efficiency. And there’s kind of other analogous cases of studies of patients who are being given dexamethasone, high dose dexamethasone just for three day courses, but they were on it for multiple courses for their to be given with their chemotherapy.15% of those patients developed adrenaline’s efficiency.

Dr. Casey Kim: Wow, so what I’m taking away is that these patients that are on multiple courses of steroids might actually benefit from a steroid taper because they are at higher risk of adrenal insufficiency, which is actually not something that I typically think about.

Dr. Shreya Trivedi: Yeah, I’m just thinking right now about all the people who I see so often come in and out of the hospital on steroid bursts and, gosh, I’ve probably missed some cases of adrenal insufficiency and probably should have taper them. So we really sit with the idea of steroids tapers, what are some best practices? How should we do this? I know it’s an art but are there any good rules of thumb?

Dr. Casey Kim: So, the principle that came up is the you can go fast until you reach a certain threshold and then you want to slow down.

Dr. Michael Weintraub: On high doses it’s okay to taper rapidly. So what’s rapidly, so every week tapering by five or 10 milligrams, and then once you get down to maybe about 20 milligrams, that’s when you have to slow down a little bit because that’s when those withdrawal symptoms can be exacerbated and then maybe decreasing by one or 2.5 milligrams per week.

Dr. Shreya Trivedi: Okay, so we can do a rapid taper until 20mg prednisone equivalent. And hold on to steroid withdrawal symptoms because we will talk about that in Pearl 5! 

Dr. Casey Kim: Yeah, and it’s a good one because I had never heard of it before this episode. Another common principle that was brought up by both our expert endocrinologists was transitioning to shorter acting steroids during the wean. 

Dr. Afreen Shariff: Anecdotally, what has worked for me and physiologically what makes most sense is to get patients to hydrocortisone and then taper them off. This seems to work more seamlessly. And physiologically it makes more sense because prednisone is a longer acting steroid and has more chances of suppressing the HPA axis that you’re actually actively trying to wake up by doing your taper. So it makes sense to switch them over to a shorter acting steroid than wears off overnight.

Dr. Shreya Trivedi: Oh, I love the idea of what we are trying to do with the taper is to wake up their adrenals that went out on vacation, right, because the patient was taking steroids. And I also love thinking about the benefits of switching to hydrocortisone, kind of brings us back, some spaced repetition to Pearl 1 where we learned that hydrocortisone is short-acting. So with hydrocortisone, the adrenals have time to kick in and aren’t suppressed as consistently as they would with a longer acting steroid like methylprednisone or dexamethasone.

Dr. Casey Kim: So if I were summarize to steroid tapers, if you have a patient that you are giving steroids for less than seven days without other recent steroid courses, feel empowered to just stop. If you’re giving steroids for longer periods of time, you can rapidly wean down to about 20 mg of prednisone equivalent and then wean more slowly and consider switching to shorter acting and less potent glucocorticoids like hydrocortisone if possible. 

Dr. Shreya Trivedi: Yeah and then I think my biggest take away is to be more thoughtful about the patients who have had a multiple short burst exposures and think about how cumulatively we might be suppressing their HPA axis and actually making them adrenally insufficient, and think a little bit more about those people who may need a cort stim test, which we will release maybe a bonus interview next week with Dr. Shariff who goes into that a bit more! 

Dr. Shreya Trivedi: So some of our discussants already brought this up in the a pearl, but what are some things that can come up when we are weaning off steroids and really limit that? 

Dr. Casey Kim: One is recurrence of disease that you were using steroids to treat and the second is adrenal insufficiency. You know, I feel like we always talk about preventing adrenal insufficiency, but I actually don’t know when or what dose of the steroid wean that we really start to be concerned about this? 

Dr. Shreya Trivedi: Yeah, that’s a good question, maybe the best way to answer this question, is to help us understand – what is a normal replacement dose or in other words what is the physiological cortisol amount our body makes? 

Dr. Weintraub: We first look at, well, what studies looked at what is the physiologic cortisol production in a 24 hour time span for patients? And the studies that we have are, there’s a few small number, small, maybe a few dozen patients, and they’re all healthy volunteers. And the average daily cortisol production, if you took take the mean is seven milligrams per meter squared of body surface area.

Dr. Shreya Trivedi: So it’s not a one size fits all. It really depends on your patient’s body surface area.

Dr Michael Weintraub: Well, if you kind of lump all the studies together, the range is about 5 to 9, the mean might be 7, the range might be 5 to 9 mg per meter squared. So that’s kind of how we get to ultimately, well how much physiologic dose for an average human, maybe 10 to 15 milligrams.

Dr. Shreya Trivedi: So in this case 10 to 15 milligrams of cortisol is the 24 hour physiologic amount that our bodies produce and we can think of it as being roughly equivalent to 10 to 15 milligrams of hydrocortisone or, for prednisone, 2.5 to 3.5 mg of prednisone daily. 

Dr. Casey Kim: Well then we can combine that physiologic dose of steroids and then how long a patient has been on a steroid and then understand who is at higher risk for adrenal insufficiency.

Michael Weintraub: In terms of duration, if someone’s on a dose of steroid for less than two weeks, they would be at a low risk of developing adrenal deficiency. Probably at any dose. But then when we get to someone’s been on a dose of prednisone equivalent for of more than five milligrams and we’re getting to somebody who’s taking it for more than two weeks, well then they might be at a moderate risk of developing it and then if it’s more than four weeks, so then they’re going into the higher risk.

Dr. Shreya Trivedi: And we will link these thresholds for adrenal insufficiency in the show notes and infographic.

Dr. Casey Kim: Yeah, definitely a good reference to have! You know Shreya, the other thing in addition to adrenal sufficiency that we worry about with weaning is steroid withdrawal syndrome.

Dr. Shreya Trivedi: Ah! Now it comes up!

Dr. Casey Kim: Exactly! We mentioned briefly in Pearl 4, but it’s a major reason that we start to really slow down the steroid taper at around 20 mg of prednisone. 

Dr. Beth Wallace: The steroid withdrawal symptoms are actually the more common and the more limiting factor. Uh, anywhere from about 10 to 80% of people who have been on prolonged steroids have some sort of withdrawal symptoms. So this is a very poorly defined, uh, entity. It gets called the steroid withdrawal symptom. It gets called quote unquote pseudo-rheumatism. Steroid dependency has been used, that term, and it’s basically a complex of symptoms that’s not whatever you started the steroids for. So it’s not the underlying condition and it’s not adrenally insufficient that make people feel bad when you taper their steroids. And the most commonly described phenotype is fatigue, general malaise, which can include things like dizziness, it include nausea, it could include abdominal pain, myalgia, often a psychiatric component, depression or anxiety.

Dr. Casey Kim: Our experts and even reviewers had a variety of metaphors to explain steroid withdrawal syndrome, all of which I thoroughly enjoyed, but my favorites were “hitting the brakes on a car going a 100 miles an hour” and “getting sick when you go on vacation after you leave work and your cortisol levels drop all of a sudden.” 

Dr. Shreya Trivedi: Ah man, I didn’t think about that, but it does happen. Your cortisol levels are all reved up trying to finish everything before a vacation, and then you suddenly plummet! As much as I love that I think the other thing really important to highlight was really how to communicate this wean to our patients and really help them through this with what to expect. 

Dr. Afreen Shariff: So the car screeches and that’s how the patients feel on the inside when you try to do that. So we have to be a little mindful and you need to educate your patients that they’re not going to feel great, especially forthe first couple days each step down. These are not days where they want to go for a marathon. These are days they really want to take it easy. When I take it easy, these are days you really want to pick up a book that you wanted to finish for a long time or you want to sit and watch your favorite Netflix series. That’s what you want to educate your patients about, and these are things you learn along the way when you take care of many patients with adrenal insufficiency and do enough steroid tapers that you understand the nuances of what patients go through and that helps you guide other patient on what to expect.

Dr. Casey Kim: Another thing that may prevent weaning steroids is that patient can be hesitant about going off steroids that have worked for them and then starting something new or more targeted, which can happen in the rheumatology world.

Dr. Beth Wallace: I’d say the most common conversation I have is like we discussed, you know, people are, people are on steroids for some autoimmune problem and they’re resistant to tapering the steroids in favor of a more targeted treatment. They’re understandably reluctant and they’re going from a drug that they feel is safe, that they’re comfortable with. They’ve often been on for a long period of time, that their doctors are very comfortable giving them that they haven’t known themselves to have any side effects from, to a drug that’s, you know, some sort of biological molecule made in a lab. I often find myself, trying to think of, um, ways to convey, you know, this other treatment is actually much more targeted and much less generally destructive than steroids. Even though steroids work. So what I always tell my patients who are very scared of going off steroids and going on, you know, biologic drugs that are much more targeted is steroids are like a bull in a China shop. They just go in there and they just, you know, break all your immune system, right? Everything, they, they freeze your neutrophils, right? They suppress your lymphocytes, They, they prevent diapedesis, they’re in there creating havoc.

Dr. Casey Kim: Can I just emphasize how much I love metaphors, again? 

Dr. Shreya Trivedi: Oh, yes, these are so good! I will definitely stealing some of them. And maybe if I can try to summarize, the biggest thing I am taking away in weaning or stopping steroids, is being mindful of recurrence of disease that might come up or steroid withdrawal symptoms, which honestly feel a lot like symptoms we see with adrenal insufficiency. Fatigue, nausea, depression, GI symptoms, you name it. And we can be especially mindful of people being at higher risk for adrenal insufficiency, especially if they’ve been on steroids for more than 2 weeks. The risk increases to moderate risk if they are on 5mg for 4 weeks or high risk if than a are on steroids for more than a month. 

Dr. Casey Kim: And this is where you really want to counsel and partner with your patient to let them know what to expect and that we’ll try to go as slowly as possible and work with them on getting them off steroids.

Dr. Shreya Trivedi: And with #steroidstewardship! That is a wrap for today’s episode. If you found this episode helpful, please share with your team and colleagues and give it a rating on Apple podcasts or whatever podcast app you use! It really does help people find us! This episode will count for CME credit with the American College of Physicians so click on the link in the show notes, answer 3 Qs and get CME Credit.

Dr. Casey Kim: This episode was made as a part of the Digital Education Track at BIDMC. Thank you to all the educators and mentors! Thank you to our peer reviewers Dr. Nick Mark and Dr. Katie Wysham. Thank you to Daksh Bhatia for the audio editing and Dr. Sam Woodworth for the accompanying graphics.

Dr. Shreya Trivedi: As always we love hearing feedback, email us at hello@coreimpodcast.com. Opinions expressed are our own and do not represent the opinions of any affiliated institutions. Thank you, take care!

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