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×Previous Next Time Stamps 02:01 Introduction 03:22 Pearl 1: Pneumonitis 13:39 Pearl 2: Colitis 24:35 P earl 3: Skin IRAEs 30:28 Pearl 4: Endocrine IRAEs (Thyroid) 35:15 Pearl 5: Endocrine IRAEs (Pituitary) CME-MOC Get CME-MOC credit with ACP! Sponsor: Glass Health Interested in integrating Glass AI into your EMR? Reach out to enterprise@glass.health . Use code “ COREIM” for one month free access of AI queries through Glass Pro. Show Notes ICI: immune checkpoint inhibitor IRAE: immune related adverse event Pearl 1 : Pneumonitis Time to onset : 1.5 to 127 weeks ; (median 34 weeks) Clinical presentation : Ranges from asymptomatic to acute hypoxic respiratory failure. Cough, dyspnea, chest pain, fever Differential : Heart failure COPD Infection Pulmonary embolism Pneumonitis (radiotherapy, chemotherapy) Malignancy ILD flare Neuromuscular disorder Sarcoidosis. Work up : Immunocompetent CT Chest with contrast (CXR insufficient) Often showed ground glass opacities in lower lobes Five different types of imaging findings have been seen: Chronic obstructive pneumonia–like Ground-glass opacities Hypersensitivity type Interstitial type Pneumonitis not otherwise specified Infectious workup Sputum culture Respiratory viral panel COVID-19 Blood culture Urine legionella Strep pneumo antigen +/- Bronchoscopy w/ BAL and biopsy Use is debated Can help to rule out infection or lymphangitic spread of tumor Immunocompromised Above work up + Fungal markers (B-glucan, galactomannan) Endemic fungal antigens TB PJP Treatment : Guidelines based on grade Grade 1 (asymptomatic/affecting one lobe or <25% of lung): Hold ICI and monitorRepeat imaging in 3-4 weeks If improved, can re-trial ICI If NOT improved, treat as grade 2 Grade 2 (symptomatic/involving more than one lobe of the lung or 25-50% of lung parenchyma) : Hold ICI Give Prednisone 1-2mg/kg/day and taper over 4-6 weeks If no improvement after 48-72 hours, treat as grade 3 and consider bronchoscopy with BAL +/- biopsy Grade 3 (hospitalization for severe symptoms or oxygen requirement/all lung lobes involved or >50% of lung parenchyma) or Grade 4 (life-threatening respiratory compromise/intubation required): Permanently discontinue ICI Give Methylprednisolone IV 1-2mg/kg/day and taper over 4-6 weeks If no improvement in 48 hours, add an additional agent such as infliximab, mycophenolate mofetil, IVIG or cyclophosphamide. Consider bronchoscopy with BAL +/- biopsy Decisions about empiric treatment with antibiotics and diuretics should be made on a case by case basis. Pearl 2 : Colitis Time to onset : 1 to 107.5 weeks (median 8 weeks) Clinical presentation : Abdominal pain, nausea, diarrhea, blood or mucus in the stool, fever Upper GI toxicity Presents with dysphagia, nausea, vomiting or epigastric pain Less common than lower GI toxicity (most commonly affects descending colon) Associated with NSAID and prolonged PPI use Differential : Infectious colitis (bacterial, viral, parasitic) Ischemic colitis Inflammatory bowel disease Radiation colitis Diverticulitis Drug-induced colitis (chemotherapy, tyrosine kinase inhibitors) Graft vs host disease in transplant patients Work up : Bloodwork with CBC, CMP, TSH Stool studies Culture C. diff, Ova and parasites CMV Norovirus Fecal inflammatory markers lactoferrin,calprotectin) Review medication list (antibiotics, prolonged PPI use, NSAID). CT scan for abscess Findings often mimic inflammatory bowel disease Mesenteric vessel engorgement Bowel wall thickening Fluid filled colon distension +/- Endoscopy and colonoscopy with biopsy Perform if Grade 2 or positive fecal inflammatory markers Patients on biologics: HIV Hepatitis A Hepatitis B TB Treatment : Guidelines based on grade Grade 1 (increase of <4 stools per day over baseline): Can continue ICI or hold temporarily until resolution of symptoms. Supportive care with hydration and medications such as loperamide if infection has been ruled out. Grade 2 (increase of 4-6 stools per day over baseline): Hold ICI until symptoms resolve to grade 1. Give prednisone 1mg/kg/day until symptoms improve to grade 1, then taper over 4-6 weeks. If no improvement in 72 hours or there are high risk endoscopic features, then add infliximab or vedolizumab. Grade 3 (increase of > or =7 stools per day over baseline/hospitalization): Grade 2 recommendations apply. Can consider IV methylprednisolone especially if concurrent upper GI inflammation. If no improvement in 48 hours, consider adding biologics like infliximab or vedolizumab. Consider permanent discontinuation of CTLA-4 agents. Grade 4 (life threatening symptoms/urgent intervention required): Grade 2 and 3 recommendations apply. Give IV methylprednisolone 1-2mg/kg/day until symptoms improve to grade 1, then taper over 4-6 weeks. If no improvement in 48 hours, consider adding biologics like infliximab or vedolizumab. Permanently discontinue ICI. Resume ICI if fecal calprotectin is less than 116 or if repeat endoscopy shows mucosal healing. Pearl 3 : Skin IRAE Time to onset : 2 to 150 weeks (median 7 weeks) Clinical presentation : Maculopapular rash Bullae Vitiligo Stevens Johnson Syndrome Toxic Epidermal Necrolysis DRESS Symptoms: ranges from itch +/- rash to fever, skin sloughing, pustules, blisters or mucosal erosions Differential : Allergic or irritant contact dermatitis Atopic dermatitis Psoriasis Seborrheic Dermatitis Infectious dermatitis (fungal, bacterial, viral) Unrelated drug rash with eosinophilia and systemic symptoms (DRESS) Work up : History and physical exam is very important including Examination of oral mucosa assessment of blisters and body surface area affected Medication list should be reviewed CBC and CMP should be obtained Dermatology may obtain skin biopsy for further evaluation Treatment : Guidelines based on grade NOTE: Vitiligo is associated with treatment response Grade 1 (rash<10% body surface area): Continue ICI and give topical emollients and/or mild-moderately potent topical steroids. Grade 2 (rash covering 10-30% BSA with or without symptoms): Consider holding ICI. Give topical emollients, oral anti-histamines and medium-highly potent topical steroids. Consider prednisone 0.5-1mg/kg and taper over 4 weeks. Grade 3 (rash >30% BSA with moderate or severe symptoms): Hold ICI and discuss with dermatology about the timeline for restarting. Give topical emollients, oral antihistamines and highly potent topical steroids. Start oral prednisone 1mg/kg/day and taper over 4 weeks. If pruritus is present without rash, you can try gabapentin or pregabalin. Grade 4 (severe symptoms requiring hospitalization): Hold ICI, Hospitalize patients and give IV methylprednisolone 1-2mg/kg/day. Discuss with dermatology/oncology about appropriateness of restarting ICI Pearl 4 : Endocrine IRAEs (thyroid) Time to onset : 1.5-130 weeks (median 14.5 weeks) Clinical presentation : Pituitary dysfunction, Hypothyroidism, Hyperthyroidism, Adrenal insufficiency Nausea, vomiting, abdominal pain, weight loss, lightheadedness or orthostasis or syncope, and profound fatigue T1DM Polyuria or polydipsia, nausea or vomiting, abdominal pain, and/or visual blurring Primary hypothyroidism C old intolerance, dry skin, constipation, weight gain, and/or fatigue Differential : Hashimoto’s thyroiditis Central hypothyroidism Post-viral subacute thyroiditis Induced by other drugs (lithium, amiodarone, anti-epileptics) Induced by head and neck radiation Work up : TSH and free T4 Low TSH and low free T4= central hypothyroidism (see hypophysitis below) High TSH and low free T4= primary hypothyroidism T3 TSH receptor antibody testing if suspicion for Graves’ Disease (ophthalmopathy or thyroid bruit). Treatment : Guidelines based on grade: Grade 1 (4.5 Continue ICI and monitor TSH every 4-6 weeks. Grade 2 (TSH>10 and symptomatic): Can continue or hold ICI Start levothyroxine Check TSH levels every 6-8 weeks until TSH is in reference range. Grade 3-4 (severe symptoms): Hold ICI until symptoms resolve. Hospital admission if concern for developing myxedema (bradycardia, hypothermia, altered mental status). Discuss with endocrinology about IV levothyroxine and steroids. Thyroid supplementation per grade 2 recommendations. Consider referring to endocrine at grade 2; should be referred at grade 3 or higher. For thyrotoxicosis: Grade 1 (asymptomatic or mild symptoms): Continue ICI. Beta blocker for symptoms. Monitor thyroid function 2-3 weeks to detect subsequent hypothyroidism (commonly occurs in transient subacute thyroiditis) in which case the patient should be treated for primary hypothyroidism. Grade 2 (moderate symptoms): Consider holding ICI, give beta blocker for symptoms. If persistent >6 weeks, will need thyroid suppression. Grade 3-4 (severe symptoms, unable to perform ADLs): Hold ICI until symptoms resolve and give beta blockers for symptoms. Discuss with endocrine about medical therapies such as steroids, potassium iodide, methimazole, propylthiouracil or surgery. Refer to endocrine if thyrotoxicosis persists for more than 6 weeks. Pearl 5 : Endocrine IRAEs (pituitary) Time to onset : Variable Hypophysitis is most commonly seen with ipilimumab . Clinical presentation : Fatigue Loss of libido Mood changes Oligomenorrhea due to hormone imbalances Headaches Visual changes Work up : AM cortisol AM ACTH TSH and free T4 Electrolytes Hormone levels: LH, FSH, estrogen and testosterone. +/- AM ACTH stimulation testing Complete IF AM cortisol results are indeterminate (between 3 and 15) +/- MRI brain with and without contrast with sellar cuts Complete if visual changes, headache or diabetes insipidus Treatment : Use Guidelines based on grade NOTE : Principles are somewhat different because hormone replacement is the mainstay of treatment instead of immunosuppression for endogenous hormone production recovery. Grade 1 (asymptomatic/mild symptoms): Consider holding ICI until the patient stabilizes on hormones. Steroid replacement for adrenal insufficiency if needed. Thyroid replacement if needed with free T4 goal in upper half of reference range. Testosterone or estrogen therapy if needed and no contraindications. Grade 2 (moderate symptoms): Consider holding ICI Hormone replacement as grade 1 recommendations If MRI shows pituitary swelling or optic chiasm compression, treat with prednisone 1mg/kg/day and taper over 1-2 weeks to maintenance therapy dose. Grade 3-4 (severe symptoms/unable to perform ADLs): Hold ICI until stabilized on hormones. IV hydrocortisone 50-100mg q6-8 hours tapered down over 5-7 days or prednisone 1-2mg/kg/day tapered over 1-2 weeks to maintenance dose. Hormone replacement as grade 1 and 2. Behind The Scenes YouTube Interview Subscribe to Core IM’s YouTube Channel for more behind the scenes, whiteboard animations and more! Transcript Dr. Benjamin Schlechter: You have to think a little bit like a bone marrow transplant doctor, they have learned an amazing instinct for how inflammation and irritation resulted in misbehavior of the transplanted immune system. So you have to have a little bit of paranoia and you have to look for subtle things when dealing with checkpoint inhibitors, when dealing with the immune system. Anytime there’s something on a scan that doesn’t make sense, you’d kind of need to explain it. And anytime someone doesn’t get better, you kind of need to explain it. Dr. Shreya Trivedi: That’s Dr. Schlecter, a GI oncologist from the Dana Farber Cancer Institute. Intro Dr. Shreya Trivedi: Welcome to the Core IM 5 Pearls Podcast, bringing you high-yield evidence-based pearls. This is Dr. Shreya Trivedi. Dr. Anuranita Gupta: And this is Dr. Anuranita or Anu Gupta, an internal medicine resident at Beth Israel Deaconess Medical Center. Today we’re doing part 2 of our podcast on immune checkpoint inhibitors and immune-related adverse events (or IrAEs). Dr. Shreya Trivedi: In the first part we set the foundation for understanding how checkpoint inhibitors work and a framework to think of the adverse events that can happen. Dr. Anuranita Gupta: In this episode, we are zeroing in on illness scripts to differentiate IRAEs from other medical conditions and we’ll share some crucial management tips too! Dr. Shreya Trivedi: It was a hard job to pick out discussants’ brains to do most common solid organ problems we encounter. Dr. Anuranita Gupta: With each of the solid organs, we will touch on the symptoms, diagnosis and management. Let’s get started with the pearls we’ll be covering. Dr. Shreya Trivedi: Test yourself by pausing after each of the 5 questions. Remember the more you test yourself, the deeper your learning gains. Dr. Anuranita Gupta: Pearl 1: Pneumonitis or inflammation of lung parenchyma. Dr. Shreya Trivedi: How do we diagnose checkpoint inhibitor related pneumonitis? Once identified how do we treat it? Dr. Anuranita Gupta: Pearl 2: Colitis or inflammation of the colon. Dr. Shreya Trivedi: How do we diagnose checkpoint inhibitor related colitis? Once identified how do we treat it? Dr. Anuranita Gupta: Pearl 3: Skin IRAEs. Dr. Shreya Trivedi: How do we recognize dermatologic adverse events caused by checkpoint inhibitors? How are these conditions treated? Dr. Anuranita Gupta: Pearl 4: Endocrine IRAEs, with a focus on thyroid adverse events. Dr. Shreya Trivedi: With checkpoint inhibitor toxicity to the thyroid, what are the different presentations and at what TSH level do you stop an ICI? Dr. Anuranita Gupta: Pearl 5: Endocrine IRAEs continued, with a focus of hypophysitis or pituitary inflammation. Dr. Shreya Trivedi: How does hypophysitis present? Do steroids help? Pearl 1: Pneumonitis Dr. Shreya Trivedi: So let’s start with a case we have seen not too infrequently! Dr. Anuranita Gupta: Mr. Johnson is a 64 year old male with hx of HFpEF and stage III non small cell lung cancer diagnosed two years ago. He has been receiving atezolizumab (a PDL-1 inhibitor) as part of his treatment plan for the past 5 months. He presents to the clinic with dry cough and shortness of breath for the past 4 weeks. On exam, he is satting 93% on room air and crackles are heard in the lower lung fields. Dr. Shreya Trivedi: There’s so much to dig into here – this could be heart failure, infection, pulmonary embolism, pneumonitis from radiotherapy or medication and lymphangitic spread of malignancy. So are there any specific characteristics of checkpoint inhibitor pneumonitis that can help us tease things out? Dr. Anuranita Gupta: So Pneumonitis, like all of the IrAEs, can present at any time, but the general rule of thumb is that pneumonitis is about 8 months after starting a checkpoint inhibitor. Dr. Shreya Trivedi: And then in terms of symptoms, I imagine there aren’t any specific symptoms to help us differentiate if it’s a pneumonitis IRAE or not . Dr. Anuranita Gupta: You are right, so someone can come in with acute hypoxic respiratory failure OR just have cough, dyspnea, chest pain or what’s crazy is some patients with checkpoint inhibitor pneumonitis. Dr. Shreya Trivedi: So we also sat down with Dr. Warner, a melanoma oncologist at the Stanford who had a pro-tip about checking an ambulatory O2 sat: Dr. Allison Betof Warner: One thing that I have found to be exceptionally useful is an ambulatory sat. So sometimes patients are sat very well and appropriately on room air at rest, and just like the old days of PCP, their oxygenation will plummet with any exercise. So I’ve found that to be very helpful and obviously as a test you can easily do in your office and that can be useful. Dr. Shreya Trivedi: Alright we will look out for ambulatory sat plummeting! What kind of diagnostic workup would you do for Mr. Johnson? Dr. Anuranita Gupta: Okay. So the approach is to really rule out the common things that we do have tests for. So I would want an infectious workup for sure. A sputum culture, respiratory viral panel, COVID-19, blood cultures and consider urine legionella and strep pneumo antigen. I would also throw in a BNP given his history of heart failure. And then for imaging I would think about chest x-ray but then would probably delete that order and order a CT chest with contrast both to rule out pulmonary embolism and see what the lung parenchyma looks like. Dr. Shreya Trivedi: Yep that’s exactly what Dr. Narjust Florez, a thoracic oncologist at Dana Farber, recommended when we sat down with her. Dr. Narjust Florez : So no checks X-ray in this case. We skip that. We go straight to CT chest and how the inflammation pattern will help you understand if it’s a ground glass, a diffuse infiltrates in both loaves, that’s a drug-induced pneumonitis. Dr. Anuranita Gupta: And from my reading, there are actually 5 different radiographic subtypes that we see with pneumonitis. Ground glass opacities in the lower lobes are the most common subtype of pneumonitis. Dr. Benjamin Schlechter: Now in this day and age, you’re usually told inflammatory processes in the lungs, ground glass, opacities, septal thickening, pneumonitis versus drug toxicity cannot rule out covid 19. And that will be the scan result that you get a hundred percent of the time. Dr. Shreya Trivedi: I just appreciate his realness that we probably can’t hang your hat on the CT scan giving the slam dunk answer. Dr. Allison Betof Warner: It can be harder on a CT as well for lung cancer patients because their baseline lung parenchyma isn’t often normal, whereas a melanoma patient often has normal baseline lung parenchyma. Additionally, then you added the complication of radiation and we occasionally radiate lung lesions in melanoma as well. And we are all sitting there pulling our hair out trying to figure out what is happening. I know that’s the thing. Dr. Shreya Trivedi: So Anu it does feel validating knowing that an oncologist may be pulling their hair too- if we’re still not sure from all of this workup if Mr. Johnson’s symptoms are from infection, cancer or pneumonitis IRAE- can we do a bronchoscopy to get more answers? Dr. Anuranita Gupta: You may have opened up a can of worms here. It turns out the role of bronchoscopy is debated in the field. Dr. Allison Betof Warner: You do sputum samples, maybe even a B A L from a bronch, it comes back, but it can come back non-infectious frequently even with pneumonia because the sensitivity of that test isn’t great. Often they’ve already gotten antibiotics before you’ve gotten the BAL, and so it may be sterile, they’re still infection there that you are already treating. Dr. Anuranita Gupta: So yeah the bronch might NOT give you a clear cut answer but of course if the BAL does pick up an infection that can be helpful or in case that a trans-bronchial biopsy does show lymphangitic spread of the cancer that can be helpful. Dr. Shreya Trivedi: Oof let’s close up that can of worms then and go back to Mr. Johnson. Say oncology sees him, sees that none of the workup has come back positive for something else, thinks of the clinical picture more and does think pneumonitis IRAE is high on the differential. With oncology’s blessing, let’s treat him for it! Dr. Anuranita Gupta: So big picture is that-treatment of IRAEs is generally guided by what grade aka what severity they are and there are usually 4 grades, with 4 being the worst Dr. Shreya Trivedi: ASCO guidelines which lay everything out clearly and is a great reference for the management of these toxicities based on that grade. Dr. Anuranita Gupta: The higher grades often reflect a higher severity of symptoms and a larger amount of lung parenchyma affected. The lack of response to treatment of a lower grade can also upgrade the toxicity to a higher grade. Dr. Shreya Trivedi: And just to give a contextualize of the severity scale, grade 3 is when the patient requires hospitalization for severe symptoms/new oxygen requirement or all lung lobes or >50% of parenchyma is affected. Dr. Anuranita Gupta: And what most internists are thinking about is do we hold the ICI temporarily or permanently? Dr. Narjust Florez: This is why I think a very good takeoff message is if you identify these immune adverse events early, it allows for the patient to maybe rechallenge in the future. Because if you identify as a grade one or grade two, you can rechallenge. But if it’s a grade three or grade four, there’s a no-no. Dr. Anuranita Gupta: And then of course, all of the management plans involve steroids in different types and doses and pneumonitis is no exception. For the highest grade, oncologists consider treating with immunomodulators like infliximab, mycophenolate, IVIG and cyclophosphamide as well. Dr. Shreya Trivedi: One helpful thing is the trajectory of checkpoint inhibitor pneumonitis. With steroids, the patient should start to feel better very soon especially at the lower grades. Dr. Narjust Florez: The difference between the COPD and pneumonitis is that they get a lazarus effect. You start the patient on prednisone and the next day you call them, they’re like, doctor, I’m doing great, doing great. So you don’t get that with COPD. It takes a little bit longer. Dr. Shreya Trivedi: But what about humble diuretics and antibiotics early on in the admission? Is there a role for them in this management plan? Dr. Anuranita Gupta: Truthfully, a lot of these cases are not clear-cut pneumonitis, and it’s not easy to rule out infection and volume overload and you end up doing a bunch of things together like steroids, antibiotics, and diuretics. Dr. Allison Betof Warner: We had a patient I remember clearly was starting to escalate to even needing high flow and was not responding to antibiotics, did have a fever which was leading us more towards the infection pathway, but inflammation can also cause fevers. We had a multidisciplinary conference. If we are letting pneumonitis fester without steroids, we are very much potentially getting into a very dangerous territory where patients can need to be intubated. And so there was a lot of concern obviously about giving steroids and lowering responsiveness to infection if this did happen to be infectious. And our infectious disease colleagues were certainly concerned about that, as was I. But at the end of the day, we really felt strongly that there was a very good chance this was also pneumonitis that was going untreated and that the patient was deteriorating. And so we did, we put them on HCAP level antibiotics as well as full dose steroids and thankfully that patient, I don’t know which one they got better in response to. Maybe it was both, but that patient did thankfully turn around. Dr. Shreya Trivedi: I appreciate ending this pearl on pneumonitis reflecting on the humbling nature of medicine, and you have to work with colleagues to figure out if you are doing too much or little. Let’s recap this pearl, Anu. What do you want people to take away? Dr. Anuranita Gupta: What I want ppl to remember is that the presentation for pneumonitis is nonspecific. One clue can be its presentation around 8 months from starting the medication. Having a CT with ground glass in the lower lobes is typical for checkpoint inhibitor pneumonitis, though many things can look like this. Also, if it is IRAE pneumonitis, the treatment- steroids- will make the patient feel better quickly at the lower grades. Pearl 2: Colitis Dr. Shreya Trivedi: Ok now that we did pneumonitis, lets move a little lower in the body to colitis. This is another tricky one because the symptoms are nonspecific and can mimic other conditions. So Anu give us a case so we can pick our experts brains on what we can and can’t hang our hats on for the the diagnosis Dr. Anuranita Gupta: Yeah let’s jump right in. Ms. Moon has a history of stage IV metastatic melanoma which was diagnosed a year ago and has been undergoing treatment for the past 2 months with Nivolumab+Ipilimumab (so that’s a combination PD-1 and CTLA-4 inhibitor). She presents to the hospital with acute abdominal pain, N/V, diarrhea with 8 stools per day and inability to tolerate oral intake. Dr. Shreya Trivedi: What to do… what to do…. For some spaced repetition from the IRAE 101 episode, with colitis IRAEs, the median time to onset is 8 weeks which fits with our case of presenting about 2 months later Dr. Anuranita Gupta: And like most IRAEs, it’s the combination checkpoint inhibitors that are the most likely to cause checkpoint inhibitor toxicity Dr. Shreya Trivedi: So in terms of symptoms, colitis IRAE, you can expect to see anywhere from a few to many of these symptoms. Dr. Benjamin Schlechter: It’s usually a sub acute onset over three or four days on these two or three days where they get watery stool, increased frequency, feel a little bit off . Dr. Anuranita Gupta: When thinking about diarrhea- other than the usual culprits that you already think of, don’t forget radiation colitis, graft vs host disease which doesn’t apply to this patient but does apply to certain bone marrow transplant patients and other drug effects such as from chemotherapy or tyrosine kinase inhibitors in this patient population. Dr. Shreya Trivedi: Remind me what are tyrosine kinase inhibitors? Dr. Anuranita Gupta: If you’re looking at a list of cancer therapies and see –tinib at the end of the name, there’s a good chance it’s a tyrosine kinase inhibitor. Dr. Shreya Trivedi: I like that the T from tyrosine kinase inhibitors and the T in tinib. Now back to the drawing board- we’re admitting Ms. Moon to the hospital. What kind of diagnostic workup will be most helpful? Dr. Benjamin Schlechter: You should check for common things like c diff, norovirus. Dr. Anuranita Gupta: Yep in addition to C.diff, norovirus I’d get TSH, stool cultures, ova and parasites. For particular immunocompromised patients, I would add on the good old CMV, cryptosporidium, microsporidium, cyclospora tests. Dr. Shreya Trivedi: That sounds good in terms of infectious workup, but for those fecal inflammatory markers like fecal calprotectin and lactoferrin Dr. Anuranita Gupta: Yeah these inflammatory markers can represent the amount of mucosal damage there has been Dr. Shreya Trivedi: So if it shows the amount of mucosal damage it may be helpful to monitor how much mucosal damage there is over time? Dr. Anuranita Gupta: Yep and fun fact if it is checkpoint inhibitor colitis, the oncologist will monitor the fecal calprotectin to see if they can restart the checkpoint inhibitor and if it’s below 116 it might be the green light they are looking for. Dr. Shreya Trivedi: Ok cool so below a certain level it helps know the inflammation has cooled down and less mucosal damage Dr. Anuranita Gupta: One thing to keep in mind is if your patient has a GI malignancies, lactoferrin and fecal calprotectin may be higher than normal anyway without colitis. Dr. Shreya Trivedi: Yeah these inflammatory markers can be high in any type of colitis so it’s not something we can hang our hats on. Dr. Benjamin Schlechter: A flex sig with tissue biopsy, we’ll be diagnostic, although that’s not a nice thing to do to someone who’s got an inflamed colon and diarrhea. Dr. Shreya Trivedi: Yeah I hear if on EGD and/or colonoscopy we find features like ulceration, that may let us know early that a biologic agent will be needed but i never know if i should pull the trigger to consult or not Dr. Anuranita Gupta: Don’t overthink it because the decision to scope is a complex and worth the multidisciplinary discussion. In general, if symptoms are mild it may be reasonable to wait for the inflammation to cool down before scoping. But if the inflammation is severe, it is recommended to scope early. Dr. Shreya Trivedi: And then last and most importantly with our diagnostic hats on, let’s look at the med rec. What should we look out for in the med rec when it comes to a patient with diarrhea who is on a checkpoint inhibitor? Dr. Anuranita Gupta: Well I would ask about antibiotics with c diff in mind and also would ask about NSAID use and prolonged PPI use since they have been linked to checkpoint inhibitor colitis. Dr. Shreya Trivedi: And then in terms of imaging, CT abd and pelvis (with or without contrast) can help in terms of the extent of colitis and to rule out an abscess. And of course, patients are allowed to have two things going on, like recently I took care of a patient whose CT scan pointed to diverticulitis so only treated that first but actually had both diverticulitis and checkpoint inhibitor colitis. Dr. Benjamin Schlechter : I think it’s very legitimate if a patient presents with diverticulitis on a checkpoint inhibitor to treat them for diverticulitis . You’re not risking anything by doing that, but be worried that either there’s something else going on or something else could go on and just think about it. You should hear that whisper in the back of your mind, what about the pembro? Dr. Anuranita Gupta: We love a good auditory hallucination! And what a great opportunity to talk about CT findings in colitis IRAE. I can’t imagine a radiology read explicitly identifying checkpoint inhibitor colitis but some clues to look for are that it often affects the descending colon. Some other buzzwords are mesenteric vessel engorgement, bowel wall thickening, and fluid filled colon distension. Dr. Narjust Florez : Let’s look at the wall of the colon. Something that’s very unique to colitis induced by immunotherapy is they have wall edema. And you can see that in diverticulitis. You see the pouches that are inflamed, but they’re individual. But here it’s a continuous wall edema and it’s a malabsorption diarrhea. That’s what it is. It’s like a crohn induced by drugs. So the malabsorption diarrhea and the patient, we told you very different than the diverticulitis diarrhea is, how did they say it in their own words? Everything just goes through me. That’s a very common phrase. Everything just goes through me because the wall has so much edema. That’s why the physiology of medicine is so beautiful. The wall has so much edema because there’s T-cell infiltration that produces this humongous amount of inflammation. So there is no way that there is any villi able to absorb anything. Dr. Shreya Trivedi: that physiology is so beautiful and makes me now want to pay more attention to the history that someone is giving and really look at the CT scan for significant wall edema. Ok now let’s talk about treatment for colitis and im sure mgmt based on grades/severity. Dr. Anuranita Gupta: For the grades, it’s all about the number of stools. Less than four stools a day, you do the typical supportive treatment for diarrhea with hydration, meds like loperamide once you’ve ruled out c.diff or dysentery and you can continue or temporarily hold the ICI until symptoms resolve. Dr. Shreya Trivedi: Speaking of which… to hold or not hold the ICI always stresses me out and some days I find myself scrambling to get a hold of the oncologist to see if it’s okay to miss a dose or not Dr. Benjamin Schlechter : There is no such thing as urgent checkpoint inhibitors. Okay? These are drugs whose onsets are in weeks to months. If you give someone a highly active chemotherapy, you could see benefit on a chemosensitive cancer in days. If you give people a highly active checkpoint inhibitor on a highly immune responsive cancer, you don’t see anything for weeks. There is no situation in which giving a checkpoint inhibitor is an emergency, and that’s also an important utilization discussion. Okay, sometimes, should we give this person inpatient checkpoint inhibitors? No, we should not. These drugs have an incredibly long half-life, usually over 20 days. Missing a dose is fine, but it’s very hard to reassure patients about that. And even doctors, I’ll be honest, I always want to order it when they’re in the hospital. You got to step back and be logical and missing a dose is okay. Dr. Shreya Trivedi: That’s helpful- now we can rest assured if a dose of this medication is missed as long. What if the patient has more than 4 stools/day above baseline and has a higher grade severity? Dr. Anuranita Gupta: Yep, for the higher grades aka more than 4 stools above baseline, we are of course going to reach for steroids (prednisone vs methylpred) and tapering over 4-6 weeks once symptoms improve. Dr. Shreya Trivedi: Wow, taper takes over a month after symptoms improve? Why so long? Dr. Allison Betof Warner: There are some patients who can do with a quick taper, but many will have their colitis flare again if you taper too quickly. So this isn’t a set it and forget it type of taper because as soon as the colitis flares again or whatever IRAE you’re treating, you have to go back up. And so this is an individual patient approach. Dr. Anuranita Gupta: I had a patient just like this and I remembered the CORE IM steroids episode and pulled up the graphic to remind myself about PJP prophylaxis, osteoporosis prophylaxis as well as GI prophylaxis with a PPI. Dr. Shreya Trivedi: Oh good throwback and connection to remember the prophylaxis! Okay that’s steroids but then I’m wondering when is colitis bad enough to reach for biologics? Dr. Anuranita Gupta: A good rule of thumb is that if symptoms don’t improve in 3 days of steroids, it’s time to pull out the big gun biologics. And for colitis are anti-TNF (infliximab) and anti-integrin (vedolizumab). Dr. Shreya Trivedi: Good to know that it’s the 3 day mark when we should be looking for backup help. What a whirlwind! Let’s recap this pearl. Yep so what i learned about IRAE colitis typically presents within 2 months of starting a checkpoint inhibitor and consists of numerous episodes of voluminous diarrhea. When working it up, we want to rule out a host of infectious causes and imaging can be helpful if there’s significant wall edema. A good nugget on mgmt is that it’s okay to hold the ICI while you are trying to sort out if it is an IRAE colitis or not. But if it’s above 4 stools above baseline, we are going to reach for steroids. Pearl 3: Skin IRAEs Dr. Shreya Trivedi: Now onto the skin. Dr. Anuranita Gupta: With my sunscreen in hand I’m ready to talk about our next case! This is Ms. Singh who has a history of stage III melanoma and was recently started on adjuvant nivolumab (PD-1 inhibitor) 3 weeks ago. She presents to the clinic with a rash that developed over the past week. Exam shows erythematous macules over the chest which are pruritic with no vesicles. Dr. Narjust Florez: It’s red macular. I’m not going to try to describe that anymore because every time an internist describes a rash, a dermatologist tears a little bit of blood somewhere, so I’m just going to at every, macco, poplar rash, that’s poetic as much as you get from me. Dr. Shreya Trivedi: Yep, appreciate the realness. As a throwback, checkpoint inhibitor toxicity to the skin can happen relatively soon. If you look at the literature, the median time to onset is around 7 weeks but our oncologists have told us they often see it pretty quickly after starting a checkpoint inhibitorlike 3 weeks for our patient Dr. Anuranita Gupta: And then the symptoms here can vary a bunch. Some patients just have an itch +/- rash, while some can have scarier symptoms like fever, skin sloughing, pustules, blisters or mucosal erosions. Dr. Benjamin Schlechter: So first of all, make sure it’s a rash and make sure it’s not itching that they scratched that it’s a rash. The next thing you want to do is look at how extensive it is. Look at the body. You really have to undress the patient and see how extensive it is and use your B S A calculations to figure out how much of the body is covered. And then critically, you must look in the mouth. If there is skin toxicity in the mouth, you need to call for help. Dr. Shreya Trivedi: Totally! Yep for the scarier stuff like bullae and are concerned about bullous dermatosis, vitiligo, Stevens Johnson Syndrome or DRESS we will of course loop in our friendly local dermatologist. For the rest of this pearl lets talk about the more common skin toxicity which is inflammatory dermatitis Dr. Allison Betof Warner: You want to ask all the typical dermatology questions, right, any new exposures, any new foods, did you change your detergent? Dr. Shreya Trivedi: Yep all good derm questions and of course my favorite as an internist is thinking about any recent medications or over the counter med changes Dr. Anuranita Gupta: Yep, all this good history can help us rule out allergic or irritant contact dermatitis, eczema, psoriasis. Dr. Shreya Trivedi: And doing a good exam to rule out infectious dermatitis like fungi with tinea, bacteria that we see in impetigo or a virus like shingles. Lots of things on the ddx Dr. Anuranita Gupta: Ok Shreya I have to share this one fact about vitiligo that I learned while researching this topic that was so interesting to me. Dr. Shreya Trivedi: Oh yeah go for it! Dr. Anuranita Gupta: So apparently, vitiligo, which as a quick reminder is the loss of skin color in patches, hints at a stronger immune response of the drug against melanoma. So basically if you see vitiligo as a toxicity, it means the checkpoint inhibitor is kicking the melanoma’s butt. Dr. Shreya Trivedi: Amazing! Okay so it’s like sorry you have these skin color patches loss but yay we are getting rid of cancer cells. So I’m curious what specific grades and management tips are out there for the skin IRAEs? When I try to force myself to think about it all I can think about is call derm. Dr. Allison Betof Warner: Your index of suspicion has to be that this is I C I dermatitis from I C I is exceptionally common and can happen quite early even after the first dose. So there is very little harm in giving topical steroids. If this is on a small enough area of the body that you can use topical steroids, I always prefer that to systemic steroids. And I don’t necessarily biopsy these patients and get dermatologic biopsies unless it appears very abnormal, it doesn’t respond to typical treatments, then I certainly pull in my dermatology colleagues. Dr. Anuranita Gupta: So for low grades in skin toxicity (that is <10% of BSA and no systemic symptoms), treatment usually involves emollients aka moisturizing treatment in addition to topical steroids. And here we can continue the checkpoint inhibitor. Dr. Shreya Trivedi: Just like lung and GI tract, with higher grades we’re treating with steroids and holding the checkpoint inhibitor. Ok so Ms. Singh probably with her grade 1 maculopapular eruption treated with topical steroids so maybe we avoided dermatology but just to say it outloud when do we think about referring to dermatology? Dr. Anuranita Gupta: Generally, refer to dermatology at grade 3 or higher, which usually >30% body surface area, but if there is any concern at all for Stevens Johnson Syndrome (SJS), DRESS or mucus membrane involvement, please refer to dermatology at ANY grade. Dr. Shreya Trivedi: Let me recap. In terms of ICI toxicity, taking a good history about exposure, meds, and ruling out infection can be helpful. Within that, look at blisters, body surface area affected, mucus membrane. If <10%, we’re doing topical steroids. So let’s recap, the history and physical exam to differentiate if its skin IRAEs or something else. In particular we should look at if there’s mucus membrane involvement, blisters and how much of the body is affected. Topical vs oral vs IV steroids may be needed to treat the IRAE among other medications. Pearl 4: Endocrine IRAEs (Thyroid) Dr. Shreya Trivedi: For pearl 4, we’re diving into the glands or the endocrine checkpoint inhibitor toxicities. We’ll be focusing this pearl on thyroid IRAEs and pearl 5 on pituitary IRAE. Dr. Anuranita Gupta: Ok let’s jump right into our case then! Picture Mr. Williams who is a 58 year old man with stage IV non-small cell lung cancer who has been receiving treatment with pembrolizumab starting 5 months ago. Just a few weeks prior he felt very hot most of the time and was having frequent bowel movements. But now, he reports he’s had recent weight gain, goes a few days between his bowel movements and feels cold despite the weather being warm. Dr. Shreya Trivedi: Wow, that sounds uncomfortable. His case fits with what we talked about in the last episode with thyroid issues often presenting with a hyperthyroid state at first, and then a hypothyroid one. Dr. Anuranita Gupta: Yep so first there’s transient subacute thyroiditis which increases the release of thyroid hormone which is why he had heat intolerance and diarrhea and later as the gland burns out, he became hypothyroid with cold intolerance, constipation and weight gain. Dr. Shreya Trivedi: Dr. Florez laid out how closely she follows a patient watching out for that transition point between that hyperthyroid to hypothyroid state Dr. Narjust Florez: First dose of pembro, nothing happens. Second dose of pembro, TSH comes to 0.01 and then you’re like, hmm, let me get the T four. So the T four is elevated. And you’re like, well, you’re in thyroiditis now you have to let you cool down, but you don’t treat it at least the patient is symptomatic. If the patient is symptomatic in the thyroiditis phase, you do have to do propranolol, you do have to do the inhibition. But then we have very close follow-up at that point. I do call my endocrinologist because there’s a very fine line when the patient is hyperthyroid and then becomes hypothyroid. Dr. Shreya Trivedi: It’s like balancing a seesaw- we have drugs at our disposal to treat symptomatic hyperthyroidism with propranolol but we need to monitor closely through the progression of the thyroid gland getting burnt out Dr. Anuranita Gupta: Totally! Going back to our case with Mr. Williams, if I had to create a differential diagnosis from his current symptoms which are in line with a primary hypothyroidism, I would include Hashimoto’s thyroiditis, post-viral subacute thyroiditis and would think about other drugs like lithium, amiodarone and antiepileptics that could be contributing. Dr. Shreya Trivedi: And for our cancer population- head and neck radiation as well as a central hypothyroidism from pituitary IRAE are on the ddx. Dr. Anuranita Gupta: And then what’s really interesting about the endocrine glands is that giving steroids like we do for the solid organ and skin IRAEs doesn’t really resolve the toxicity. Dr. Allison Betof Warner : The thing that’s different about endocrinopathies is that they tend to be permanent. That once whatever gland is affected is affected, it tends to stop making their hormone even if you aggressively treat the inflammation. Dr. Shreya Trivedi: Well that’s really unfortunate. Glands can’t bounce back the way solid organs do but sounds like these patients do just fine with being on hormone replacement. Dr. Anuranita Gupta: But the exception to being on hormone replacement is if its grade 1 thyroid toxicity . And grade 1 means asymptomatic with minimal TSH elevation. Here you would just continue the ICI and monitor the TSH Dr. Shreya Trivedi: Okay then with grade 2 or higher that is which is going to be a TSH >10 milli international units/L and symptomatic – we hold the checkpoint inhibitor for grade 2 or higher and start levothyroxine at that point too. Dr. Anuranita Gupta: Part of monitoring here is checking both TSH and T4 levels. The free T4 usually normalizes sooner than the TSH so it’s better to check both at once. Dr. Shreya Trivedi: Once the TSH and T4 levels are back to normal ranges, the levothyroxine should be continued since the gland doesn’t bounce back and the thyroid function tests can be checked every 6 months or a year. Dr. Anuranita Gupta: And that’s a wrap on thyroid IRAEs. Let’s recap this pearl. Thyroid IRAE usually presents with as a transient hyperthyroid state followed by a hypothyroid one. Dr. Shreya Trivedi: And then for management, yes there is the ASCO guidelines for graded management that we will link in the show notes but big takeaway for the thyroid gland being affected is permanent and just giving steroids will not resolve it so ultimately these patients need levothyroxine. Pearl 5: Endocrine IRAEs (pituitary) Dr. Anuranita Gupta: Now onto the pituitary gland and its IRAE which is called hypophysitis. Dr. Shreya Trivedi: Why do they call it hypophysitis? Why can’t they just call it pituitary-itis? Dr. Anuranita Gupta: That would be too easy, Shreya. Dr. Shreya Trivedi: Hypophysitis ! Let’s solidify it with a case! Dr. Anuranita Gupta: This one is about Ms. Thompson, a 59F with stage IV renal cell carcinoma, who was treated with ipilimumab and nivolumab (CTLA-4 and PD-1 inhibitors) 1.5 years ago. She now presents to the hospital with fatigue, headache, N/V. Over the last week, she experienced episodes of dizziness. Dr. Benjamin Schlechter : So when I see a patient in a clinic with kind of the dwindles, they’re just not right. Their electrodes are a little bit off. They’ve got the hyperkalemic metabolic acidosis kind of funny, something’s wrong. They often are hyponatremic, they’re not eating well, they’re kind of weak and dizzy. You worry about endocrinopathy. Dr. Shreya Trivedi: There so many hormones that the pituitary makes, a patient can present with so many different symptoms and conditions and in this case i’m thinking about adrenal insufficiency– those vague symptoms fatigue, n/v, dizziness Dr. Anuranita Gupta: So true. You know Shreya when I’m thinking about the hormone axes and specifically the pituitary gland- I always think back to learning the FLAT PiG mnemonic in med school to remember the anterior pituitary hormones of FSH, LH, ACTH, TSH, prolactin and growth hormone. The posterior pituitary too and that makes oxytocin and ADH. Dr. Benjamin Schlechter : Hypophysitis is not the most common, definitely the most dramatic. They often have that tunnel vision thing you learn about in doctor school where they bounce off the doorframe, and when you ask them, they will say, oh yeah, it’s so weird. I keep hitting my shoulder on the door. I had a patient who worked at Home Depot and he’s like, I kept bumping into the racks. Dr. Shreya Trivedi: Oh man, yes we definitely ask good Qs and listen really well to see if we pick on the visual changes – right because that means the optic nerve is being affected from physical compression. Dr. Anuranita Gupta: Definitely. So what’s the diagnostic workup we’re getting for Ms. Thompson and these vague symptoms if we are concerned about hypophysitis? Dr. Benjamin Schlechter : So you’re going to check your TSH and your free T four because you might have high in the axis thyroid dysfunction. You want to check your A C T H I check prolactin because sometimes prolactin is actually really high or really low. Maybe cortisol, random cortisol and am cortisol, and if you see evidence of this sort of hypo Pitt presentation, it’s probably a hypophysitis. Dr. Shreya Trivedi: We CAN also think about getting LH, FSH, estrogen and testosterone but if there aren’t overt symptoms of hormone imbalance, we may not need these Dr. Benjamin Schlechter: You can often prove it with an M R I with a pituitary protocol, but you can also prove it by labs. And that’s probably faster than getting an M R I in a lot of cases. Dr. Anuranita Gupta: And that’s an MRI brain with and without contrast with sellar cuts and you are especially going to want to get that if there are red flags for visual changes Dr. Allison Betof Warner: So early sitis, so brand new imaging, you can actually see on a dedicated brain M R I, you have to get thin cuts through the pituitary. If there is acute inflammation that you’ve caught early, there is a thought that pulse dose steroids might be able to rescue some of those patients to maintain some endocrine function. Dr. Shreya Trivedi: Ok so not to bury the lead but her labs showed TSH and free T4 were normal but her AM cortisol of 1.2 ug/dl and low ACTH so both are low, which suggests a central process higher put in the pituitary rather than a primary adrenal insufficiency at the level of the adrenal gland (where ACTH would be high.) Dr. Anuranita Gupta: And then unsurprisingly her MRI showed pituitary enlargement with inflammation. Dr. Shreya Trivedi: Now that we know we’re dealing with hypophysitis let’s talk grades. The grading here is a bit subjective because it depends on the severity of symptoms and how a patient may describe it. Dr. Anuranita Gupta: That’s true… and but the difference here is that treatment really depends on which hormone axes have been hit. Dr. Shreya Trivedi: For example, we can talk about how we would give levothyroxine for thyroid replacement and testosterone and estrogen therapy if there are no contraindications like prostate or breast cancer respectively. Dr. Anuranita Gupta: But in our patient, we know that the adrenal axis was hit so we could give hydrocortisone or prednisone for the secondary adrenal insufficiency (and again, its secondary because it’s affecting the pituitary gland, not the adrenal gland). Dr. Shreya Trivedi: And if there are vision changes from the optic chiasm being compressed from pituitary swelling, we would certainly be reaching for higher dose steroids and taper over 1-2 weeks to a maintenance therapy dose. Dr. Anuranita Gupta: Let’s recap this high yield pearl on Hypophysitis. It can present with a wide range of symptoms given all of the hormones affected by the pituitary gland. In addition to evaluating hormone levels, headache and visual changes are clues that should prompt MRI imaging of the pituitary gland. Dr. Shreya Trivedi: Once hypophysitis is identified, hormone replacement is a major part of treatment; however, if there is pituitary swelling or the optic nerve is compressed, more potent steroids have to be given to preserve vision. Ending Dr. Anuranita Gupta: That wraps up our clinical pearls on immune checkpoint inhibitor adverse events. Dr. Shreya Trivedi: 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! Dr. Anuranita Gupta: This episode was made as part of the Digital Education Track at BIDMC. Thank you to all the educators and mentors! Thank you to our peer reviewers Dr. Meng Wu and Dr. Sharon Elad. Dr. Shreya Trivedi: Thank you to Jerome Reyes for the audio editing and Dr. Cathy Cichon for the accompanying graphics. 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. References Qian Qin et al. Type, timing, and patient characteristics associated with immune-related adverse event development in patients with advanced solid tumors treated with immune checkpoint inhibitors. JCO 38, e15160-e15160(2020). Naidoo J, Wang X, Woo KM, et al. Pneumonitis in Patients Treated With Anti-Programmed Death-1/Programmed Death Ligand 1 Therapy [published correction appears in J Clin Oncol. 2017 Aug 1;35(22):2590. Bryan J Schneider et al. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update. JCO 39, 4073-4126(2021). Hua C, Boussemart L, Mateus C, et al. A ssociation of Vitiligo With Tumor Response in Patients With Metastatic Melanoma Treated With Pembrolizumab. JAMA Dermatol . 2016;152(1):45-51. Ryder M, Callahan M, Postow MA, Wolchok J, Fagin JA. Endocrine-related adverse events following ipilimumab in patients with advanced melanoma: a comprehensive retrospective review from a single institution. Endocr Relat Cancer . 2014;21(2):371-381. Published 2014 Mar 7. The post Immune Checkpoint Inhibitor Adverse Events 2.0: 5 Pearls Segment appeared first on Core IM Podcast .…
Time Stamps 01:27 Anion Gap Metabolic Acidosis (Dr. Nick Villano) 02:52 Inhaler Delivery Systems (Dr. Allie Sheridan) 04:53 IDA in Pregnancy (Dr. Michael Auerbach) Transcript Dr. Shreya Trivedi: Hi everyone. Happy holidays. What a year 2024 has been. This has been quite a year of growth. On the personal front, our family grew. We had another baby boy and I relearned all about the newborn days with a 4-year-old running around on the Core IM front. This was also a year of growth. We expanded to other platforms, particularly on YouTube. And so we thought this time at the end of the year, it would be good to look back at some of the fantastic teaching that came from some of the video teaching. We’ll go through and hear clips from our favorite one from the outreach group, one from the whiteboard animations team. And then lastly, one from the behind the scenes interview crew. So three in total. So first step is Dr. Nick Villano, who started a series for just in time teaching called Just in the Nick of Time. Yes, pun intended with his name. One of my favorites that I’ve pulled up multiple times on rounds now is the one he did on Anion Gap Metabolic Acidosis with the GOLDMARK mnemonic. Now, I think we’ve all known the GOLDMARK mnemonic for a long time, but I just love the nuances that he added to it. And he actually writes gold on one side of the paper and marks on the other side of the paper. And this allows him to group it in a way where he can actually remember the big buckets, the alcohols, the over-the-counter meds and the metabolic causes of anion gap, metabolic acidosis. So let’s play a clip from him going over the over-the-counter meds that cause anion gap, metabolic acidosis. ANION GAP METABOLIC ACIDOSIS Dr. Nick Villano: Let’s move on down to the next box. O and a. O is for oxoproline ( 5-oxoproline) , and all you need to know is that that’s a metabolite of Tylenol or Tylenol. If you want to stress the O to make it stick, A is for aspirin, but use this to remind yourself that other salicylates can cause anion gap acidosis too. This includes bismuth subsalicylate or Pepto Bismol and methyl salicylate, which is found in some topical pain medications like Bengay. So this is the OTC or over the counter medication box. Over ingestion of these medications can lead to acidosis in the blood and sending an early serum tox screens is important to make an accurate diagnosis. Dr. Shreya Trivedi: And again, we’ll link in the show notes, the five minute video going over the whole gold mark mnemonic and all the nuances he adds to it. Alright, next up is our favorite pick from the whiteboard animations team inhaler delivery systems. Now I just feel like the content is so relevant. I mean, think about the number of patients we’ve had come in for asthma and COPD exacerbations, and how often do we actually ask them to show us how they’re taking their daily home inhalers and if they’re doing so appropriately. So let’s play a short clip from Dr. Alliei Sheridan on how do you counsel patients to use their inhaler with a PMDI system? How do you know if your patient has a PMDI system? Well, on the med work, you’re going to look if their inhaler ends with HFA. So for example, albuterol, HFA in their med rec. INHALER DELIVERY SYSTEMS Dr. Allie Sheridan: PMDIs have medication stored in a pressurized canister. The PMDI needs to be shaken. And if it’s a new inhaler or it hasn’t been used for several days, then it needs to be primed. By pumping the canister two to three times. You have to coach patients to inhale and press down on the canister. At the same time. Doing this can be technically challenging, so it’s a good idea to watch them and give them feedback on how they’re using their inhaler. And last but not least, and maybe most important of all is to tell patients to hold their breath for 10 seconds after the medication is released in order to get a full dose. Dr. Shreya Trivedi: Yes, hold their breath for 10 seconds after. I can’t emphasize that enough. And of course the visuals make it a lot easier to follow and it’s a great six minute teaching that you can even give to your patient. And it also covers how to properly use dry powder inhalers or soft mist inhalers. We will link in our show notes, but please go check it out. Okay, last but not least. We realized with the podcast that we had all these wonderful parts of the interviews that never made it on air, mostly because we have to be so mindful of the cognitive load of each episode. But one interview I still remember so vividly till today is Dr. Michael Auerbach. He is the man that wrote the IV iron page on UpToDate and just is full of these zingers. I mean, he has this fierce advocacy when it comes to implications of iron deficiency in pregnancy. And I have had so many colleagues, so many friends, men, women who really had to advocate when they were having a child to get, for example, a ferritin checked or give IV iron despite having a hemoglobin of nine and being so symptomatic, extremely fatigued in the second trimester. I think it’s just sad to see that we have just kind of accepted as a society that women will have to suffer during this time. I again love Dr. Auerbach’s advocacy and my ears especially perked up when he talked about even the implications of iron deficiency on the fetus. And this part of the interview, honestly, was so good. I had a hard time picking just a clip, so I’ll just let Dr. Auerbach take the floor. IDA IN PREGNANCY Dr. Michael Auerbach: The fact of the matter is that iron deficiency in women is rampant. I can tell you I don’t know anything about you and I’m not going to ask you any personal questions. I can tell you right now if I were to do a bone marrow on either of you right the second, there’s a 60% chance it would have no sustainable iron. And if either of you have a child, move that number to about 85. Okay, so that’s a fact. It’s a longstanding issue. So it’s really time that we address it. Preconceptual iron sufficiency is something that is absolutely essential. And iron deficiency at any week of gestation or at least anemia, has been associated with a statistically significant increment in spectrum disorders in the baby. So let’s take a pregnant woman walks into her OB and goes, hi, I’m pregnant. Fair number of tests are ordered, and they should be. They check for syphilis, gonorrhea, aids, hepatitis, measles, rubella liver functions, and they do A CBC. But if you’re not anemic, they don’t check an iron study. They don’t even get a ferritin or if you’re non-anemic. So the United States Preventive Services Task Force says there’s insufficient evidence to recommend routine screening for iron deficiency in the absence of anemia. That’s so outrageous. It borders on negligence. The prospective studies, one of which I had the privilege to do, shows that 50% of you, 50% of women presenting gravitas in the first trimester are iron deficient based on serum ferritin percent transferrin saturation or both. When you get further into pregnancy, that number goes much higher. 25% are severe, 40% are never diagnosed. It’s outrageous that we don’t do a ferritin diagnosis. So in pregnant women, non anemic iron deficiency is present in half. That means 50% of you are ignored. Ignored. That’s the right word. I think we’re going to fix that. Figo just published an entire supplement, and I had the privilege of writing one of the sections, which is really the management of pregnant and non gravid iron deficiency where we talked about the importance of preconception iron repletion, intrapartum iron repletion, and stressing that it’s much more important to deal with intrapartum iron sufficiency rather than postpartum iron repletion. Babies born iron deficient have measurable decrements in behavior, cognition, motor function, and brain development. To give you an idea how outrageous this truly is, we don’t check babies for iron deficiency at birth. We have their cord blood, we have it. It’s in our hands. All we have to do is check off the ferritin, but we don’t, b ut iron deficiency occurs at a level associated with measurable developmental decrements in one in four. Dr. Maria J. Fernandez Turizo: How do you choose between oral treatment versus IV treatment? Dr. Michael Auerbach: All right, well, now we have to define who I am. I’m extremely polemic. I think oral iron is ridiculous. Okay, fer, sulfate’s fine. Fer, fumarates fine. But if you have inflammatory bowel disease, heavy uterine bleeding, chronic kidney disease, collagen vascular disease after bariatric surgery or pregnancy where oral iron doesn’t get to the baby doesn’t get to the baby, the data’s there. And now, if you would’ve done this interview two months ago, I would’ve said, the big problem I have is that we don’t have proof that IV iron does. Now we do. It was just published in the American Journal of Obstetrics and Gynecology, MFM, Awomolo, A-W-O-M-O-L-O, as the first author. The senior author, I believe is Megan Hill and Ivy and not Oral Iron corrected the baby’s Ferritins. Now, what we don’t know is that going to make a difference in development, but our anemia study, which is called RAPID Iron in India, over 4,300 women accrued finished, will have the last delivery of those 4,300 women in about eight weeks, and we should have our first set of data in February. The second phase of the study is called Rapid Iron Kids , about a thousand babies, all of whom had ferritins. They’re going to get MRIs to look for brain morphology, and we really believe we’re going to show a difference in development in the babies who got IV compared to oral iron. I hope. Dr. Shreya Trivedi: Hope that would be amazing. What a game changer for the world. Dr. Michael Auerbach: Yeah, this is a game changer. It’s time. I was just in Switzerland last week. I was invited by the World Health Organization to talk about setting up a platform for the administration of IV iron to pregnant women in lower and middle income countries. But I’m telling you, I don’t know that I’m going to live long enough to get the World Health Organization to move their behind. Dr. Maria J. Fernandez Turizo: Hopefully, that’s all very inspiring. So basically, pregnant women should not receive oral iron. Dr. Michael Auerbach: Not after the first trimester. Now in the first trimester, that’s the only iron I prescribe, not because IV iron is dangerous in the first trimester because there’s no safety data with IV iron in the first trimester, I’ve treated 9,000 pregnant women and I have zero serious adverse events and zero negative baby outcomes. If either of you think that there’s a significant difference between zero and one, we have a philosophical difference, zero is the number that I need to live with. So I’m not going to mess around with trimester number one. I tell them to take one iron pill every other day till 14 weeks, and then I give IV iron. And if I said, if you can’t tolerate it, just don’t take it. Eat iron rich foods and I’ll give you IV iron at week 14. Dr. Shreya Trivedi: And you could find more of Dr. Auerbauch as well as other content from brilliant guest experts that didn’t make it on air on our YouTube channel. And credit to Dr. Alice Kennedy that leads this. We’ll link more to these in the podcast app as well as in the show notes. We hope you’ve enjoyed this potpourri of the best of that exists outside the podcast series. Please go check out our YouTube channel that we’re building up subscribe. As always, we welcome feedback. We hope you have a fantastic start to your 2025. Please take this time to celebrate yourself and how far you’ve come. The post Best of Youtube 2024: Anion Gap Metabolic Acidosis, Inhaler Use, Iron Deficiency in Pregnancy appeared first on Core IM Podcast .…
Expert hematologist and UpToDate author on iron deficiency anemia and IV iron treatment, Dr. Michael Auerbach explains the severe sequelae of iron deficiency during pregnancy as well as how to treat and prevent it. Behind The Scenes Videos Key Points 50% of first-trimester pregnant women experience iron deficiency. One in four infants are iron deficient at birth, which correlates with significant neurological sequelae. Oral iron does not correct iron deficiency in neonates. Clinical trials investigating the impact of neonatal iron repletion on neurological outcomes are ongoing. There is no safety data for IV iron during the first trimester. During the second and third trimesters, IV iron is both safe and effective. Interested in learning more on the topic of iron deficiency anemia (IDA)?: Explore our IDA YouTube playlist here Check out the full podcast episode at: https://www.coreimpodcast.com/2024/03/27/fe-deficiency-treatment-5-pearls-segment/ Original interview by Shreya P. Trivedi MD and Maria J. Fernandez Turizo MD. Video content and editing by Alice Kennedy MD. The post Iron Deficiency in Pregnancy: Behind the Scenes Videos appeared first on Core IM Podcast .…
Time Stamps 02:13 Define the problem / Clinically important bleeding Outcome/Risk benefit /Risk factors] 05:58 Hx and H2 antagonists 10:42 SUP-ICU 15:12 PEPTIC 19:30 REVISE trial 27:28 Deprescribing 29:06 Outstanding questions Sponsor: Freed is an AI scribe that listens, prepares your notes, and writes your note in < 30 seconds. Freed learns your style over time and is HIPAA compliant! Join over 9K clinicians who love Freed and saves them hours a day! Use the code CORE50 to get 50% off your first month with Freed . Show Notes Background How common are stress ulcers in the GI tracts of critically ill patients? Mucosal ulceration is common in ICU patients (75% detected by endoscopy) but often is asymptomatic But what is “ clinically important bleeding ?” Defined as either: Bleeding causing hemodynamic compromise e.g. drop in 20mmHg BP, rise in 20 bpm HR Drop in Hb of 2g/dL or requiring ≥2 units blood transfusion Clinically important bleeding occurs in ~1.5% of patients In previous eras, death from clinically important bleeding was much higher 50% death from clinically important bleeding in 1994 80% death from clinically important bleeding in 1980 Stress ulcer prophylaxis started in the late 1970s, when physicians used nasogastric antacids, which numerically reduced GI bleeds. What are risk factors for stress ulcer bleeding in ICU patients? Mechanical ventilation Coagulopathy Shock Liver disease/cirrhosis Guidelines In 1999, the critical care prescribing guidelines recommended H2 blockers or sucralfate as stress ulcer prophylaxis Grade C, based more on expert opinion rather than robust clinical trial data Based on 1998 ranitidine study which showed IV ranitidine reduced the risk of clinically important bleeding in ICU patients without an effect on mortality. It raises the question of whether a checklist-mandated treatment like stress ulcer prophylaxis should be implemented based on low certainty evidence and a grade C weak recommendation? PPI trials SUP-ICU , NEJM 2018 PPI (40 mg pantoprazole IV) versus placebo In ICU setting – 80% of patients were mechanically ventilated Primary outcome: all-cause mortality at 90 days Secondary composite outcome were “clinically important events” including: clinically important bleeding, pneumonia, C. difficile infection or myocardial infarction Results: No difference in all cause mortality between PPI v placebo (RR 1.02 [95% CI 0.91-1.13], p=0.76) No difference in clinically important events (RR 0.96; 95% CI 0.83-1.11) What about clinically important GI bleeding within the composite outcome? 2.5% in PPI arm vs. 4.2% in placebo arm (RR 0.58; 95% CI 0.30-0.86) *But be wary of subdividing the composite outcome The trial was not powered to show a difference in this component of the composite alone! No differences in adverse events Subgroup analysis: stratified by illness severity score SAPS II In patients with SAPS II score >53, the risk of death appeared higher: RR 1.13 (0.99-1.39) *But be wary of the limitations of subgroup analysis They should be considered hypothesis generating and not definitive answers as we make decisions in patient care. PEPTIC trial , JAMA, 2020 Cluster crossover randomised controlled trial, PPI vs. H2 antagonists The unit of randomisation was each ICU Each ICU unit was randomised to use PPIs or H2 blockers for 6 months Then each ICU unit swapped over to the other drug for 6 months Each ICU acted as its own control and all other variables (ex. enteral feeding, mobilisation, antibiotic use) were presumed constant, creating theoretically optimal experimental conditions 50 ICUs included, 26,828 patients- all patients mechanically ventilated Primary outcome: 90 day all-cause mortality Results: No difference in all cause mortality at 90 days (RR 1.05; 95% CI 1.00-1.10) Clinically important bleeding appeared lower in PPI arm (RR 0.73; 95% CI 0.57-0.92) but this was a secondary outcome that the trial was not powered to analyze Harms: no difference in C. difficile infection and length of stay in ICU between groups Major limitation Contamination : 20% of those ICUs randomised to H2 blockers used PPI instead Can look at per-protocol analysis i.e. analyse the results based on what treatment the patients actually received But limitations of per protocol analysis: violates randomisation, reduces sample size, loss of generalizability, may overestimate the efficacy. REVISE trial RCT of patients who were mechanically ventilated in 68 ICUs, n=4821 PPI pantoprazole 40 mg IV versus matching placebo Two primary outcomes- Efficacy : clinical important GI bleeding at 90 days Safety: death due to any cause at 90 days New feature- secondary end-point included a patient-important bleeding outcome Derived using a mixed methods study in conjunction with patients who had recovered from ICU admission and their families Investigators were trying to work out what events really matter to patients This included: any blood transfusion, vasopressor treatment, diagnostic endoscopy, CT scan, surgery, death, prolonged hospitalization or disability. Results: Significant reduction in clinically important bleeding (HR 0.30; 95% CI 0.19-0.47, p<0.001) No difference in death at 90 days Reduced patient-important bleeding Subgroup analysis by severity score: no subgroup differences seen when stratified by severity score Harms? No difference in ventilator-associated pneumonia, no difference in C. difficile infections between groups Meta-analysis of PPI stress ulcer prophylaxis trials Included 12 trials, examining PPI versus placebo for stress ulcer prophylaxis 9533 participants, but mostly represented REVISE and SUP-ICU Results PPIs reduced clinically-important GI bleeding (RR 0.51, 95% CI 0.34-0.76) – high certainty of evidence PPIs had no effect on mortality (RR 0.99; 95% CI 0.93-1.05), low certainty of evidence Subgroup analysis by severity In low severity subgroups*: PPI appeared to reduce the risk of death (RR 0.89, 95% CI 0.80-0.98) In high severity subgroup: uncertainty re: direction of effect on death, but cannot exclude risk of harm (RR 1.08, 95% CI 0.96-1.20) *various different severity scores were used: SAP II used in SUP-ICU, APACHE used in REVISE Discussion/Takeaways We finally have high-certainty evidence that stress ulcer prophylaxis with a PPI reduces clinically-important bleeding compared to no prophylaxis in mechanically ventilated patients in a contemporary ICU setting Suggestion that PPIs also reduce events that patients care about, which was assessed with a novel endpoint called patient important bleeding outcome PPIs do not appear to reduce the risk of death for all ventilated patients in the ICU The effect on death may be too small and the occurrence of death from stress ulcer bleeding too rare to detect any effect in a RCT There is still uncertainty about subgroup effects, especially in those with the highest severity scores- suggests the possibility of harm from the meta-analysis and SUP-ICU and PEPTIC, but not in REVISE Transcript Dr. Shreya Trivedi: Welcome to Beyond Journal Club, a collaboration between Core IM and NEJM Group. Dr. Greg Katz: The goal of Beyond Journal Club is to take landmark clinical trials and put them into context. Telling the story of how we got to where we are, what it means for our patients, and how we take care of them. Dr. Shreya Trivedi: I’m Dr. Shreya Trivedi, an internist at Beth Israel Deaconess Medical Center. Dr. Greg Katz: I am Dr. Greg Katz, cardiologist at NYU. Dr. Sarah Gorey: And I’m Dr Sarah Gorey, an editorial fellow at New England Journal of Medicine Dr. Shreya Trivedi: And this may the first time we have had a friend from overseas from the wonderful and green land of Ireland. Dr. Sarah Gorey: I’m honoured to be the first, and hopefully not the last! Today we are talking about the REVISE trial, which was published in the July 4th issue of the New England Journal of Medicine in 2024. Dr. Shreya Trivedi: And put it out there, what did the REVISE Trial ask? Dr. Sarah Gorey: REVISE asked the question, do proton pump inhibitors aka PPIs prevent stress ulcers … and do that without causing harm in intubated ICU patients? Dr. Greg Katz: My first thought when I was considering this trial was how many of us just get a prompt that we should be ordering stress ulcer prophylaxis and then we click sign and it makes me cynical to see that the evidence behind many of our most common practices isn’t always all that strong. And so it’s worth diving into whether PPI prophylaxis is like too many other things that we do in medicine: built on a house of cards worth of flimsy evidence. Dr. Shreya Trivedi: Haha I love that imagery, I feel that should have been the cover art for the House of God book. Dr. Sarah Gorey: So before we dive into the story behind this trial, let’s just review exactly what a stress ulcer is and make sure we are clear about what type of patients are at risk. Dr. Shreya Trivedi: Then we will discuss the story of acid blockade and the prior evidence that supported the use of PPIs in the first place. Dr. Greg Katz: And finally we’ll discuss how the REVISE trial can impact our patient care, particularly with deprescribing even if we are not intensivists or rotating through ICU. NO. 1 – Define the problem /Clinically important bleeding Outcome/Risk benefit/ Risk factors Dr. Greg Katz: I have to start with a confession here – I’m not sure that I *really know* what a stress ulcer is. I thought that gastric ulcers were caused by H pylori or too many NSAIDs, not stress. Dr. Sarah Gorey: Don’t stress Greg- so the difference is really simple- stress ulcers can develop in the GI tract during a critical illness. Dr. Shreya Trivedi: I was really surprised to learn how common these stress ulcers actually are. If you were to do an endoscopy on all the ventilated patients in an ICU, you’d find some level of mucosal erosion is over 75%. Dr. Sarah Gorey: Yes, but just because there’s mucosal erosion , it doesn’t mean someone is definitely going to bleed… so we should stress (how many times can I make that joke)… anyway so point is- bleeding from stress ulcers can be a wide spectrum from barely detectable occult bleeding to massive GI haemorrhage. Dr. Shreya Trivedi : So Sarah, what did you learn about the past studies on stress ulcers? Dr. Sarah Gorey: Well (I nearly did get a stress ulcer because) studies of stress ulcers and GI bleeds were kind of the wild west – they had all these different definitions for bleeding events… Dr. Shreya Trivedi : OH that prolly made it hard to define the problem and if we are aren’t on the same page on what exactly we are talking about, we couldn’t really find effective solutions. Dr. Sarah Gorey: Exactly. It took until the 1990s when the the Canadian Critical Care Trials Group ( which incidentally is the team behind the REVISE trial, they defined the term clinically important bleeding – to mean overt bleeding from stress ulcers that was associated with either 1) hemodynamic compromise. Dr. Greg Katz: So that’s a drop of 20mmHg in BP or a rise of 20 bpm in heart rate Dr. Sarah Gorey: Or 2) a drop in hemoglobin of more than 2g per deciliter and/or need for transfusion of 2 units of blood. Dr. Greg Katz: They found clinically important bleeding (so remember that is the ones that led to HD instability or transfusion) in critically ill occurred in about 1.5% of patients. So it’s not as common as we might think. Dr. Shreya Trivedi: So yes even though clinically important bleeding is rare, I do want to point the mortality rate from a clinically important bleeding even was nearly 50% – so these bleeds are a really big deal for the small group of patients who develop them Dr. Sarah Gorey: Wow. That’s pretty high. And so the Canadian Critical Care Trials group, I like what they did was in the 1990s as they suggested a risk-benefit ratio for individual patients. They proposed that stress ulcer prophylaxis should be given to those at highest risk. Dr. Shreya Trivedi: Sounds like they were ahead of the curve in personalized medicine in trying to tailor to the highest risk Dr. Greg Katz: Unfortunately the era of truly personalized medicine is still in the future, which makes me think of the joke that personalized medicine is the future and it always will be. Dr. Shreya Trivedi: Another realistic take on medicine! I love it Greg! The two risk factors they identified for clinically important stress ulcer bleeding were 1) respiratory failure (requiring mechanical ventilation) and 2)coagulopathy. And further studies have added two other categories: 3rd group being shock and the 4th being cirrhosis increasing risk for clinically imp bleeding Dr. Greg Katz: I look at that list of risk factors and I think, duh, sicker patients are sicker. Dr. Sarah Gorey: So let’s pause & recap: stress ulcers are common in critically ill patients, but under 2% actually have clinically important bleeding, which means hemodynamic compromise or needing a blood transfusion. And the risk factors for bleeding are mechanically ventilation, coagulopathy, shock and liver disease. NO. 2 – Hx and H2 antagonists Dr. Shreya Trivedi: So we know patients in the ICU often have mucosal erosion and that sometimes that mucosal erosion can lead to clinically significant bleeding. So it makes sense to me that something as a PPI should theoretically work. But let’s dive into that theory and step back what’s been the story behind stress ulcer prevention? aka what is the evidence? Dr. Sarah Gorey: So… the 1st studies date back to the late 70s. And you won’t believe it, Shreya, but they gave liquid antacid (a magnesium/aluminium solution) down the NG tube and they would aspirate gastric contents to make sure the pH was above 4. Dr. Shreya Trivedi: I can’t help but feel for that intern responsible for monitoring gastric pH overnight with that NG tube Dr. Sarah Gorey: I know! And it must have been pretty unpleasant for the patients too! But the mortality rate from stress ulcers in the 1970s exceeded…a whopping. 80%. So even a really labor intensive process may have made sense. Dr. Greg Katz: And what did these studies show? Of course patients treated with liquid antacids have numerically less GI bleeds. Dr. Sarah Gorey: But these studies were small single site studies so take this with grain. Dr. Greg Katz: And maybe the most important thing to keep in mind is that so much about the care that we provide in the ICU has drastically changed over the past generation. Think about it – ventilator technology is totally different, we feed patients and mobilize patients much earlier, and we’re so much better at recognizing and treating sepsis Dr. Shreya Trivedi: Yeah and these days, we’re much more aware of the dangers of prolonged steroids which we know contribute to stress ulcers. Plus endoscopy- the way that we treat these acute bleeds – is just wildly better. Dr. Greg Katz: I’m of the mindset that almost every practice in medicine should come with an expiration date before we need to generate new evidence to support the continued use of an ongoing intervention as the rest of our practice evolves. Dr. Shreya Trivedi: Yeah so let’s see if the evidence for antacids holds up or expires as our practices change. Dr. Sarah Gorey: The next wave of trials looked at the H2 antagonists. Dr. Shreya Trivedi: In 1998 a trial published in NEJM which showed that ranitidine (given IV) was better than sucralfate (given PO or via NG) at preventing GI bleeding in ventilated ICU patients. (Bleeding rates were 1.7% in the ranitidine arm compared with 3.8% in the sucralfate arm.) Dr. Sarah Gorey: Yeah and acid suppression doesn’t come without risks. , From these early studies, we started to notice there may be a higher risk of aspiration pneumonia. The theory is if you raise the gastric pH too much, the stomach might be colonised by gram negative bugs increasing the risk of aspiration pneumonia. Dr. Shreya Trivedi: Thankfully these studies looked at actual rates of pneumonia. Dr. Sarah Gorey: Yep so what that study showed is there was no difference in rates of pneumonia between the two groups. Dr. Shreya Trivedi: Ok so this is some reassurance that IV H2 blockers don’t increase pneumonia risk by increasing gastric pH and facilitating aspiration pneumonia. Dr. Greg Katz: The takeaway from that 1998 ranitidine study is that H2 blockers can be used safely and effectively for stress ulcer prevention in high risk ICU patients. Dr. Shreya Trivedi: So first of all, I didn’t know H2 blockers were strong enough to prevent ulcers. I think of them as the backup player we call in when we run into adverse rxn to PPIs. Dr. Sarah Gorey: Yes- it’s nice to know that h2 blockers do work and in 1999, they were included in the 1st stress ulcer prophylaxis guidelines, which said you could use either H2 blockers or sucralfate Dr. Greg Katz: But the strength of the recommendation was graded as C, meaning the evidence supporting the recommendation was somewhat limited. Dr. Shreya Trivedi: So far we’ve been talking all about H2 blockers and sucralfate, but our current practice is PPIs so when did PPIs enter the scene? Dr. Sarah Gorey: So…there were a few under-powered trials looking at PPIs and stress ulcer bleeding but because these were small studies they didn’t add significantly to the evidence base. And can you believe it wasn’t until 20 years later, in 2018 when we started to have stronger evidence for PPI use. Dr. Greg Katz: So all of us who wrote orders for PPIs for intubated patients before 2018 were making decisions based on the transitive property – H2 blockers work so PPIs should work too. But that’s making clinical decisions based on level of evidence C a lower quality of evidence than we should aspire to use in our practice. maybe a bit just fore. NO. 3 – SUP-ICU Dr. Sarah Gorey: Yeah, it really surprised me that it took until 2018 for the SUP-ICU trial which was published in NEJM in December 2018 and investigated PPI versus Placebo in an ICU setting Dr. Greg Katz: Hold on a second. Versus Placebo? But we literally just talked about how H2 blockers work better compared to sucralfate and were guidelines recommended? why did they not compare PPI to H2 antagonists? Or even sucralfate?. Was that ethical? Dr. Sarah Gorey: That’s a good point Greg. but remember,while stress ulcer prophylaxis was a guideline recommended in 1999 and the strength of that recommendation was pretty lukewarm. By the time this study was done, there was a sense in the ICU community that actually ICU care had improved so much, with early enteral feeding, and that stress ulcer bleeding was just not common and not a major clinic risk anymore. Dr. Shreya Trivedi: And I remember at that time there was all this buzz with new observational evidence linking PPI use with nosocomial infections and C.diff, and i know we talked about aspiration pneumonia, but there was concern that PPIs might cause harm Dr. Sarah Gorey: Yeah like you said earlier Greg,it was like the “expiration date” had run out for stress ulcer prophylaxis. Dr. Greg Katz: Ok so it sounds like there was enough clinical equipoise with both the unclear benefits of acid blockade given improvements in ICU care, along with the possible harms of PPIs. What did SUP-ICU aim to show? Dr. Sarah Gorey: SUP-ICU wanted to see if PPI prophylaxis would reduce death at 90 days. Dr. Greg Katz: All-cause mortality a super ambitious endpoint – and I give the investigators credit for trying to show a benefit on all-cause mortality. But there’s something odd about that to me – we know that stress ulcers are pretty rare, and that means mortality from stress ulcer bleeding, even though its very high, is going to be pretty uncommon. Dr. Sarah Gorey: And that’s why SUP ICU recruited 3298 patients, which is an impressive number for an ICU trial. But unsurprisingly, this trial failed to show any difference in mortality at 90 days between PPI and placebo. Dr. Shreya Trivedi: And looking at the potential harm of PPIs, SUP-ICU did something a little different and made a compost endpoint which was -clinically important GI bleeds (what we really care about) AND all the bad stuff we were worried about — pneumonia, C-diff and MI into a composite outcome, and also showed no difference in these events between the two arms. Dr. Greg Katz: The data looks better when we look at what I would have chosen as the endpoint for this study: JUST the clinically important bleeding rates. Not surprisingly, clinically important bleeding rates appeared to lower in the PPI arm (2.5%) compared to the placebo arm (4.2%) But in order to that, we would have split up the composite which always makes it statistically questionable to interpret. Dr. Shreya Trivedi: And another food for thought is one of a post-hoc subgroup analysis. I know about Greg’s soapbox about that subgroup analysis is just hypothesis generating (indeed as noted this was a post-hoc analysis), but it’s interesting to look at the signal seen in the subgroup with highest illness severity. Dr. Sarah Gorey: How do ICUs commonly define illness severity? Well, they use scores- and points are counted for things like low blood pressure, low urine output, degree of derangement of pH or electrolytes). So when you mean the subgroup of sickest patients here, Shreya, you mean those with the highest severity score points. Dr. Shreya Trivedi: Yeah thank you for that context: So when you look at the sickest group, they actually had an increased risk of mortality when treated with PPI. Yeah that definitely me pause, but again – it’s a subgroup, there was no clear biological explanation for why the sickest might be harmed by PPIs compared to sickest that didn’t have PPIs, so just food for thought. Dr. Greg Katz: Right rather than anything conclusive that should direct patient care. But yeah what I’ll take from this trial that PPIs may reduce clinically important bleeding compared to placebo but they might not have a net positive outcome for all patient groups. And since we already knew clinically significant bleeding from stress ulcers in ICU is pretty uncommon, I’m not sure that we’re truly learning anything to alter our practice. Dr. Shreya Trivedi: Haha very real Greg NO. 4 – PEPTIC Dr. Shreya Trivedi: You know I’m still thinking about those H2 blockers, especially if PPIs have been linked to possible harms. Were there any studies that compared H2 blockers vs. PPIs? Dr. Sarah Gorey: Well kind of… The PEPTIC study was published in JAMA in 2020. This was a cluster crossover RCT- where whole ICUs were randomised to either using PPI or H2 antagonists for stress ulcer prophylaxis in all their ventilated patients for 6 months; and then each unit swapped over to use the other drug for 6 months. Dr. Greg Katz: That’s such a cool way of studying a question like this because it allows for each ICU to act as its own control where the only thing that should change is the intervention drug. Dr. Sarah Gorey: Now, the primary outcome in PEPTIC was also mortality at 90 days, which as we already discussed, makes the likelihood of seeing a difference pretty small given the low event rate. Dr. Shreya Trivedi: Don’t tell me- there was no difference in 90 day mortality between the ICUs when they get PPIs vs. when they H2 blockers? Dr. Sarah Gorey: You got it Shreya! But when they actually looked at clinically important bleeding rates as a secondary endpoint, PPIs had a slightly lower bleeding rate than the H2 blocker arm (But the difference was only half a percent!) Dr. Shreya Trivedi: Nice, so a win for PPIs! They’re supposedly better so I’ve been waiting for them to show up Dr. Sarah Gorey: Wait, don’t get too excited because, we have to mention a major problem when looking at the results of the PEPTIC study, which is there was contamination between the clusters: so 20% of the ICUs who should have been using H2 blockers, actually used PPIs instead. Dr. Shreya Trivedi: Oh no that’s a problem. A crossover rate that high almost makes the results uninterpretable. What did the PEPTIC study show about the difference in harms btw PPI vs. H2 blocker? What was the signal there? And again idk if the results are not as interpretable given the amount of contamination? Dr. Greg Katz: Greg: So in the paper, I went over the per protocol analysis to better assess the signal of harm from what actually happened to patients who received PPIs or H2 blockers.. A per protocol analysis — Looking at what drugs people actually got. Dr. Shreya Trivedi: But I learned in the BJC colonoscopy episode that we need to be careful in any per protocol analysis – when we just analyze the results based on who got which drug rather, we lose the magic of randomization and our ability to infer causality is really limited. Dr. Greg Katz: And so even those limitations of inferring causality, a per protocol analysis can still point to interesting signals about both benefits and harms Dr. Sarah Gorey: Yeah appreciate that caveat.. but it is reassuring to know that in the per protocol analysis, there was no difference in rates of C diff infection and length of ICU stay between the two arms Dr. Shreya Trivedi: Yay another small win for PPIs not giving ppl more c.diff or longer length of stay from other complications Dr. Greg Katz: Leaving the contamination in cross over and per protocol discussion aside, you want to know what’s concerning to me about the PEPTIC results? Dr. Shreya Trivedi: What? Dr. Greg Katz: PEPTIC found that same link between illness severity and worse outcomes with PPI that we saw in SUP-ICU. Dr. Shreya Trivedi: Wait again? The sickest patients on PPIs had a higher mortality! Dr. Greg Katz: Typically I think of medical interventions with benefits as having the most benefit in the sickest. There’s something fascinating about the possibility that acid suppression for the ICU patients actually follows a U-shaped curve where its about finding a sweet spot Dr. Greg Katz: With our medical interventions there is usually the most benefit in the sickest patients so there is something bizarre about PPIs being associated with harm in the sickest patients – perhaps there is something fascinating about a U-shaped curve and a sweet spot where PPIs help and do not cause harm. Dr. Shreya Trivedi: Hm so bizarre and I’m curious to see if REVISE will show that too. So, to summarize the big ICU trials so far looking at acid suppression, there’s some old evidence saying H2 blockers are better than sucralfate, and then we had a multi-decade gap before SUP ICU and PEPTIC suggested that PPIs might reduce clinically important bleeding but don’t save lives for intubated ICU patients. Dr. Sarah Gorey: Exactly. OK so, that brings us up-to-date to the REVISE trial NO. 4 – REVISE Dr. Sarah Gorey: The REVISE trial randomised 4821 ICU patients to either IV PPI or placebo. Participants were followed up for 90 days. and there were two outcomes – the primary efficacy outcome was clinically important GI bleeding and the primary safety outcome was any death. Dr. Greg Katz: I’m sure that statisticians were glad to hear we have bleeding as a primary outcome this time in addition to a primary safety outcome of 90 day all-cause mortality Dr. Sarah Gorey: The REVISE trial recruited patients from 8 countries from both community hospitals and academic medical centers, so it’s a diverse patient and hospital population Dr. Shreya Trivedi: So looking at those diverse patients of REVISE – These patients were about 58 years old, 36% were female, ¾ were medical patients as opposed to surgical or trauma patients. The most common reason for admission to the ICU was respiratory disease, and most were on no acid suppression prior to their ICU admission. And just to paint the picture, all of these patients were mechanically ventilated and 70% were on vasopressors or inotropes. Dr. Sarah Gorey: I t sounds like a pretty sick group of patients that you could find in any medical ICU… The patients were randomized to either 40mg of IV pantoprazole daily or placebo treatment. They continued the treatment for 90 days or until the patient was no longer intubated. Dr. Greg Katz: I’m fascinated that the comparison was placebo but we already went over the argument for that based on how changing ICU care has created clinical equipoise about whether acid suppression is truly beneficial in ICU patients. Sarah, do you wanna do the honors of telling us what the results showed? Dr. Sarah Gorey: So yes, bleeding rates were significantly lower in those treated with PPI. Bleeding rates were 1% in the PPI arm compared to 3.5% in the placebo arm, with a HR of 0.3 and a p<0.001. Dr. Greg Katz: You don’t need a masters in statistics to know that a P value of less than 0.001 is statistically significant and the reduction in clinically significant bleeding from a PPI was very unlikely to be due to chance. Dr. Sarah Gorey: Yep and you’ll be relieved to learn that there was no difference in 90 day mortality between the two arms with mortality rates of 29% and 30% Dr. Shreya Trivedi: Keeping in mind the potential negative impact from PPIs, what about pneumonia and c diff infections? Dr. Sarah Gorey: It was pretty reassuring in terms of safety outcomes too! There were no differences in the rates of ventilator associated pneumonia (which happened in about a quarter of patients in groups, and no differences in rates of C.diff infection (which occurred in about 1%) in both groups. Dr. Shreya Trivedi: Yay PPIs making a comeback after such a bad rap that got on the streets out there back in the day Dr. Greg Katz: Everything happens in medicine at pendulum Dr. Sarah Gorey: One of the other things about REVISE that’s really quite innovative is that the investigators created a new outcome to define success in terms of things that are important to our patients… the aptly named “patient important bleeding.” Dr. Shreya Trivedi: Yeah i love that, what came out of the focus groups of patients who had survived that ICU as being outcomes they really mattered to them in their experience? Dr. Sarah Gorey: The patient-defined outcome included if the patient got any transfusion at all (remember the clinically important bleeding outcome requires transfusion of 2 units), Also included needing vasopressor treatment, diagnostic endoscopy, need for a CT scan or surgery as well as prolonged hospitalisation, long-term disability, and death. Dr. Shreya Trivedi: This is such a good idea to have a patient-centred outcome and is something we really need to see more of in RCTs. Yeah for us a trip for an urgent CT scanner may not be a big deal we just order but for the patients and families can be stressful. I remember bringing my 3 year old to a CT scan which was unnecessary for him but was still the most traumatic days of my life. So Sara what did they find those patient centered outcomes for those who got a PPI vs. placebo in the ICU? Dr. Sarah Gorey: PPIs did significantly reduce this patient-important outcome: the rate was 1.5% in the PPI arm versus 4.2% in the placebo arm…which is about a 60% relative risk reduction in things that patients really care about. Dr. Greg Katz: Okay, so to summarize, we finally have some pretty strong evidence that a daily PPI reduces clinically important GI bleeding and patient-important outcomes in a contemporary ICU population of intubated patients. Kind of crazy to think that it’s taken us until 2024 to be really confident that a daily PPI helps our mechanically ventilated patients but the data from REVISE is really compelling to me. Dr. Shreya Trivedi: Yeah! Despite it being on ICU checklists for ever! Yeah one last thing to round out REVISE is I’m wondering about that signal for harm in the sickest illness severity patients that we saw in SUP ICU and PEPTIC. Did REVISE show a similar pattern? Dr. Sarah Gorey: So reassuringly… there was actually no signal in REVISE of increased risk of death in those patients with the highest severity scores. Dr. Shreya Trivedi: Wait a plot twist in the story! But in a good direction! Dr. Greg Katz: This is a good lesson about why we shouldn’t interpret subgroup analyses as definitive – yes, there was a signal warning us about PPIs in our sickest patients from the prior trials, but we don’t see that signal in REVISE. And so I’ll reiterate the point I feel like I’m constantly making – subgroup analyses are hypothesis generating, and they really shouldn’t be practice changing on their own. Dr. Sarah Gorey: I like how you stressed that point Greg!…. But before we get carried away, we have another source of information – the REVISE investigators also did a meta-analysis of trials for stress ulcer prophylaxis which is worth looking at. Dr. Shreya Trivedi: So, this meta-analysis includes 12 trials of PPI v placebo in ICU, including ~9000 (9533) participants. but ¾ of these participants are made up of REVISE and the SUP-ICU trials. Dr. Sarah Gorey: And to no one’s surprise the meta-analysis confirmed that PPI use reduced the risk of clinically important bleeding by half. aaaand There was no effect on mortality, Dr. Greg Katz: And the meta-analysis also showed that there was no differences in risk of pneumonia or C.diff with PPI treatment Dr. Shreya Trivedi: Nice I’m glad to see there is no increase of PNA or c.diff badness pan out across all the studies we’ve seen so far. again maybe we can take that bad rap off the table. I’m glad I know that’s what the internists are concerned about looking over the med list. But what about that subgroup of ppl that had the highest severity illness scores, did the meta-analysis give us some new information about PPIs in the sickest? Dr. Sarah Gorey: When they stratified by severity in the meta-analysis, there was a suggestion that PPI use DID reduce the risk of death in those with LESS severe disease (RR 0.89, CI 0.80-0.98) but it found PPIs MAY increase mortality in those with more severe disease Dr. Shreya Trivedi: Wait what no? I thought PPIs were on the winning train. Kind of a feel like a whiplash here Dr. Sarah Gorey: It’s a brain melt, but the fine print caveat is that for those with higher severity scores in the meta-analysis- the confidence intervals crossed 1 so we actually can’t be certain whether PPIs were helpful or harmful. Dr. Greg Katz: My take home from the REVISE trial, is that we can be pretty confident that PPIs reduce bleeding and improve outcomes that matter to patients for intubated ICU patients. That elephant in the room is that question of why the sickest patients may have a signal for higher mortality is perplexing – they don’t get more c diff, they don’t get more aspiration pneumonia, so what’s the biologic explanation for why PPIs might increase risk of death for the sickest patients? Dr. Shreya Trivedi: Yeah, I don’t know. I dont think anyones knows right now. NO. 6 – Conclusions Dr. Shreya Trivedi: OK final recap of what we learned from this long stressful journey (well hopefully not stressful for the listener and this journey has been fun on the receiving end) through trials of stress ulcer prophylaxis in the ICU? Dr. Sarah Gorey: First off, PPIs reduce clinically significant GI bleeding in critically ill ventilated ICU patients compared to a placebo. Dr. Greg Katz: And I will buy that , PPIs may even have a mortality benefit in a correctly selected population due to the way that they reduce clinically important bleeding, but the magnitude of that mortality benefit is just so tiny that we’re never going to see it in a clinical trial because stress ulcer bleeds causing death is just incredibly rare. Dr. Shreya Trivedi: And second, PPI stress ulcer prophylaxis does not increase the risk of C.diff or ventilator associated pneumonia. Dr. Sarah Gorey: And lastly,I still find that subgroup signal in the sickest patients concerning… the meta-analysis was not able to exclude harm of PPIs in this subgroup with confidence – so I’m not ready to rule out that PPIs may have some risks in sicker patients. NO. 6 – Deprescribing Dr. Shreya Trivedi: So maybe to round out our discussion with how most internists interface with PPIs which is probably the choice to refill or deprescribe a PPI. Dr. Greg Katz: Yeah, PPIs are one of the most widely prescribed drugs and we need to be aware of ‘indication creep’ Dr. Shreya Trivedi: Haha I love that. Sure now we agree that PPI prophylaxis of stress ulcers in ventilated patients in the ICU is a good idea, but can we just talk about if these trials can help us with when we should be deprescribing the PPIs? Dr. Sarah Gorey: Yeah so all of these trials were really short- only 90 days or 3 months. And also were performed in ventilated patients only. Dr. Shreya Trivedi: So the investigators stopped mandating the treatment with PPIs when patients were extubated? Dr. Sarah Gorey: Yep so we can really consider the indication for the PPI is being intubated, and once the patient is extubated that indication goes away, Dr. Shreya Trivedi: And it reinforces that those of us getting patients bumping out of the ICU can feel empowered to stop the PPI if there isn’t another good reason for it. Dr. Greg Katz: The guidelines would agree with you. They recommend that critically ill patients with risk factors for stress ulcer formation should receive either PPI or H2 antagonist prophylaxis. They also recommend this should be discontinued when critical illness is no longer present or the risk factors is no longer present (remember those ventilated, those with coagulator, shock and liver disease. They also recommend discontinuing stress ulcer prophylaxis before transfer out of the ICU. NO. 6 – Outstanding questions Dr. Shreya Trivedi: To close out, what about the unknowns and unanswered questions that we have in the stress ulcer prophylaxis story? Dr. Sarah Gorey: For me, I’m stressed out about that really big unanswered question -about the sickest patients and that signal for harm we talked about Dr. Greg Katz: For the time being, I suspect REVISE will be the final word on this subject, so I’m not sure we are ever going to get a clear answers to that unanswered question Dr. Sarah Gorey: That’s so true Greg. A large trial recruiting the sickest patients in ICU to investigate the effect of PPI prophylaxis is not really going to be ethical or feasible. Dr. Greg Katz: I’m going to take a more meta conclusion from this trial – we should be demanding a higher quality level of evidence for even our most mundane clinical practices like the PPIs on our checklist. I am so thankful that the Canadian Critical Care trial group was willing to spend the time studying the question in REVISE. Dr. Shreya Trivedi: Yeahm when we order PPIs for our critically ill patients, we can do it with more confidence behind it with data and not just because it’s in some checklist o rim getting some EMR nudge or I’m getting call delinquent Dr. Greg Katz: We owe it to our patients to be consistently demanding that the evidence base supporting our decision making is strong and we should be comfortable thinkin that our clinical practices should have an expiration date, especially as medicine and technology change the context Dr. Sarah Gorey: And you could argue that the evidence bar should be even higher when we are implementing something automatic in our order sets – if the EMR is going to imply that this is an obvious treatment, then we should be demanding that the data are pretty ironclad. Dr. Shreya Trivedi: Can you imagine if the reason behind a clinical trial was that “the data for this practice reached its expiration date?” that would be really inspiring way to advance our evidence base Dr. Sarah Gorey: And I hope more trials will do the hard work to ask patients about what really matters to them and include “patient important endpoint” from patients’ lived experiences and not just what may matter to us as doctors or what the hospital gets dinged on. Dr. Greg Katz: And that is a wrap for today. If you found this episode helpful, please share with your team and colleagues and give us a rating on Apple Podcasts or whatever podcast app you use. It really does help people find us. Dr. Shreya Trivedi: Thank you to Dr. Jimin Hwang for the accompanying graphic and to Jerome C. Reyes for the audio editing. Dr. Sarah Gorey: If you have any feedback, please email us at Hello At Core IMpodcast.com Dr. Shreya Trivedi: Opinions expressed are our own and do not represent the opinions of any affiliated institutions. References Mutlu GM, Mutlu EA, Factor P. GI complications in patients receiving mechanical ventilation. Chest. 2001 Apr;119(4):1222-41. Cook DJ, Fuller HD, Guyatt GH, Marshall JC, Leasa D, Hall R, Winton TL, Rutledge F, Todd TJ, Roy P, et al. Risk factors for gastrointestinal bleeding in critically ill patients. Canadian Critical Care Trials Group. N Engl J Med. 1994 Feb 10;330(6):377-81. Priebe HJ, Skillman JJ, Bushnell LS, Long PC, Silen W. Antacid versus cimetidine in preventing acute gastrointestinal bleeding. A randomized trial in 75 critically ill patients. N Engl J Med. 1980 Feb 21;302(8):426-30. Cook D, Guyatt G, Marshall J, Leasa D, Fuller H, Hall R, Peters S, Rutledge F, Griffith L, McLellan A, Wood G, Kirby A. 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