Hello, and welcome to today's Journal Club Spotlight on Pharmacy webcast, which is supported by the Society of Critical Care and Medicine's CPP section. My name is Ava Cascone. I'm a clinical pharmacy specialist in neurocritical care at Boston Medical Center in Boston, Massachusetts. I will be moderating today's webcast. A recording of this webcast will be available to registered attendees. Log in to mysccm.org and navigate to the My Learning tab to access the recording. A few housekeeping items before we get started. There will be a Q&A after each of today's speakers. To submit questions throughout the presentation, type into the question box located on your control panel. You will also have the opportunity to participate in several interactive polls. When you see a poll, simply click the bubble next to your choice. You may also follow and participate in live discussion on Twitter following the hashtags SCCMPPJC and PharmICU. Please note the disclaimer stating that content to follow is for educational purposes only. And now I'd like to introduce your speakers for today. Each will give a 15-minute presentation followed by a Q&A. Our first presenter today is Shelby McCamey, PGY-2 critical care pharmacy resident at Ohio Health, Riverside Methodist Hospital in Columbus, Ohio. She will present on aggressive or moderate fluid resuscitation and acute pancreatitis. Our second presenter is Paige Miller, PGY-2 critical care pharmacy resident at the University of Texas MD Anderson Cancer Center in Houston, Texas. She will present on continuous infusion versus intermittent infusion of vancomycin in critically ill patients undergoing continuous veno-venous hemofiltration, a prospective interventional study. And our third presenter is Hannah Hickson-Bah, PGY-2 critical care pharmacy resident at Cleveland Clinic, Hillcrest Hospital in Mayfield Heights, Ohio. She will present acetazolamide in acute decompensated heart failure with volume overload. And now I'll turn things over to our first presenter. Hello, everyone. My name is Shelby McCamey, and I am so excited to be able to talk to you all today about aggressive or moderate fluid resuscitation and acute pancreatitis. The objectives for this presentation are going to be to review the literature and guidelines that surround fluid resuscitation in acute pancreatitis, which I'll be referring to as AP throughout the presentation. I'm looking to describe the methods and results of the trial at hand, and then really discuss and apply how this article will affect our pharmacist's recommendations for acute pancreatitis. So just to dig into the background a little bit about why we care about fluid resuscitation in acute pancreatitis. So our patients have a lot of reasons to be volume depleted when they experience an episode of acute pancreatitis. Pancreatitis causes abdominal pain and discomfort, which can reduce our oral intake and cause vomiting. Pancreatitis is also an inflammatory process that can damage our endothelium and cause capillary leakage and third spacing subsequently. And then sweating from all the fevers, inflammation, and pain can also be a source of fluid loss. This definitely explains why we have found that early fluid resuscitation decreases systemic inflammatory response syndrome, or SIRS, incidence of organ failure, and decreased admission to the ICU. We have a few guidelines that attempt to help us direct our fluid resuscitation to certain goals, the first one being the 2013 American College of Gastroenterology Guidelines. They suggest an aggressive regimen of hydration of 250 to 500 milliliters per hour, just a flat rate. There's no specific study that does support this rate of no, so it is a weak recommendation. They do also recommend to assess the fluid status at frequent intervals. And overall, they support some literature for BUN and hematocrit goals when titrating our fluid resuscitation. The second guideline is the 2018 American Gastroenterological Association Institute Guidelines, which are even more vague. They recommend goal-directed therapy for fluid management. And they cite utilizing markers such as heart rate, mean arterial pressure, central venous pressure, urine output, and then again, our BUN and hematocrit to direct our fluid goals. Now, these guidelines are definitely in contrast to what we're used to in the sepsis guidelines, which I think of a weight-based 30 mLs per kilo fluid resuscitation goal. So this really poses the question, should we be doing weight-based dosing in pancreatitis as well, since it's such a similar inflammatory process? And these guidelines are based off of very scant literature. Based on speaking of scant literature, there are very few studies that look at aggressive versus moderate fluid resuscitation in acute pancreatitis. And studies have only looked at this as a secondary outcome. So in 2010, we had our first study that compared a hematocrit goal of less than 35% to a hematocrit goal of greater than or equal to 35%. And they found an increased incidence of sepsis and in-hospital mortality in the aggressive group. Now, Singh in 2017 came along and compared aggressive versus moderate fluid resuscitation. And they found no difference in the number of interventions required between these two groups. So you can see there's a bit of a contrast. And then in 2019, a study was released by Yamashita and colleagues that compared aggressive and moderate fluid resuscitation. And they found increased mortality in the aggressive group. So you can see we've had conflicting studies throughout select literature. And not even that, but also very different definitions of aggressive and moderate fluid resuscitation and the outcomes that they are measuring. So I think that this study that I'm going to be talking about today really has a great regimented process for deciding what to use for fluid resuscitation in acute pancreatitis. And it looks to answer that question, should we be using more patient-directed goals, more weight-directed fluid resuscitation to adequately prevent severe disease and also prevent fluid overload? So this study looked at the primary outcome of development of moderately severe or severe acute pancreatitis. Secondary outcomes included incidents of local complications, such as pancreatic necrosis, persistent SERS, incidents of ICU admission, organ failure, and death. They also looked at the safety outcome of fluid overload, which is defined as two out of three criteria being symptoms, physical signs of fluid overload, or imaging, evidence of hypovolemia. Mild was defined as having a response to therapy. Moderate was defined as having a responsive therapy, but having a PF ratio dip below 300 at least once. And severe fluid overload required mechanical ventilation. So this study was a multi-center trial in India, Italy, Mexico, and Spain. It was an open-label, parallel-group, superiority, randomized-controlled trial. They included patients who were adults with a diagnosis of acute pancreatitis who presented to the hospital within 24 hours of symptom onset. And the diagnosis of acute pancreatitis was based off of the Atlantic Ocean. And the diagnosis of acute pancreatitis was based off of the Atlantic Criteria. They excluded patients who presented to the hospital with already moderately severe or severe disease, certain chronic conditions that could be exacerbated by fluid resuscitation, and certain electrolyte abnormalities that could also be worsened with fluid resuscitation. Lastly, they excluded patients with a life expectancy less than one year. In all, they randomized patients one-to-one to either the aggressive or moderate fluid resuscitation group. The aggressive fluid resuscitation group received a minimum of 48 hours of fluids. And they initially received a 20 mL per kilo bolus and a 3 mL per kilo per hour infusion. The moderate fluid resuscitation group, on the other hand, received a minimum of 20 hours of fluids. 20 hours of fluids. And they received a 10 mL per kilo bolus only if they were hypovolemic. And then they started the rate at a lower rate of 1.5 mL per kilo per hour. Now, for the two groups, they calculated a sample size of 744, be it 372 in each group, for 80% power detect as 10% difference and an alpha of 0.05. So, as you can see, with a population of 122 in the aggressive group and 127 in the moderate group, we did not meet that goal. And the trial was actually stopped early because they saw risks in the aggressive fluid resuscitation group. Moving on, for each group, there were checkpoints for fluid overload at 3 hours, 12 hours, 24 hours, 48 hours, and 72 hours. And at each of these checkpoints, they decided if patients fell into one of these three groups. The first being hypovolemia, whereas the aggressive group received another 20 mL per kilo bolus and remained at a maintenance of 3 mL per kilo per hour. The moderate fluid resuscitation group received a smaller bolus of 10 mL per kilo and then that same maintenance rate of 1.5 mL per kilo per hour. If patients were normovolemic, the aggressive fluid resuscitation group dropped them down to a maintenance IV of 1.5 mL per kilo per hour, and the moderate fluid resuscitation group had the same rate. The two groups were the same if patients were deemed to have fluid overload. They were instructed to decrease or stop the infusion. As for the baseline characteristics, they found that there was 10% more gallstone pancreatitis in the aggressive fluid resuscitation group and 6% more met SIRS criteria, which could lead to worse outcomes in that group. But importantly, there were no differences in the BISAP score, which reliably predicts pancreatitis mortality. The PAN-PROMIS score, which is the PAN-PROMIS score, showed that the PAN-PROMIS score was the PAN-PROMIS score, which is a patient-reported outcome scale based on patient symptoms, and there's no difference in the Carlson comorbidity score, which predicts 10-year survival in patients with multiple comorbidities. As for the results of the trial, they found that there were no differences between the aggressive and moderate fluid resuscitation groups in incidents of moderately severe or severe pancreatitis, severe pancreatitis alone, local complications, persistent SIRS, ICU admission, organ failure, or death. As you can see, the percentages trended better towards the moderate fluid resuscitation group in all of the categories, actually. But again, the study was underpowered to detect a difference in a lot of these categories. The one spot where there was a significant difference was in fluid overload, where they found that aggressive fluid resuscitation resulted in significantly more fluid overload than moderate fluid resuscitation. I believe that some of the strengths of this study are that it does have a diverse patient population across multiple countries. I do appreciate that the Safety Monitoring Board included a clinical pharmacologist, left the representation, a gastroenterologist, and a cardiologist. I actually liked that it was non-conforming to guideline recommendations, as I feel like those guideline recommendations weren't well supported. And I also thought that this was an appropriate monitoring time frame for the outcomes that we were looking for. The study also followed guideline recommendations for choice of fluid, which would be lactation ringers, and nutrition guidelines, which, as we know, can affect the outcomes in pancreatitis. The study was really limited by its exclusion criteria, primarily being the comorbidities. I feel like we could see more adverse effects of fluid resuscitation if we included patients who did have heart failure and things like cirrhosis that could be exacerbated by fluid resuscitation. We also excluded patients who have moderately severe or severe acute pancreatitis at baseline, so we cannot apply the study to those more severe patients who may benefit from a more aggressive regimen. Again, the trial was stopped before the goal enrollment, so a lot of those outcomes were underpowered to assess a difference, and a type 2 error could have occurred. There's also no comparison of Glasgow Emory scores, which most reliably determines the severity of pancreatitis, with a positive predictive value of 79%. They also excluded measures of fluid resuscitation, such as passive leg raise, central venous pressure, and inferior vena cava ultrasound, which would have been more objective measures to use for assessment of fluid resuscitation. There's also no correlation with fluid overload with adverse outcomes, so we know that these people got fluid overloaded, but we don't know if that actually affected their course of treatment. All in all, the author concluded that aggressive fluid resuscitation did not improve outcomes, and it was associated with a higher risk of volume overload. I think the main takeaway from this presentation is not to necessarily do aggressive or moderate fluid resuscitation, but to individualize your fluid resuscitation to your patient. It's obviously very important to start early with your fluid resuscitation to decrease mortality, but that doesn't mean that we have to fluid overload all of our patients. I think this is definitely going to make me think twice about giving lots of fluids, especially in patients who do have exacerbating comorbidities, and maybe thinking about still doing the aggressive regimen in patients who have more severe pancreatitis. I really did appreciate that the study had a weight-based protocol. It's something that I think I could implement into my practice while reassessing our fluid status frequently. I think this is a study that we'll likely see in the next acute pancreatitis guidelines, so I'm excited to see it there. Now I'm going to get into my polling questions. I would really love to know, what type of protocol does your institution use for fluid resuscitation in acute pancreatitis? Is it fixed dose like our guidelines? Is it weight-based like the study used? Is it goal-based based on BUN or hematocrit or MAP goals? Or do you not have a protocol or a different protocol? Okay, so we have a lot of folks who have no protocol for fluid resuscitation in acute pancreatitis. And I think I would kind of agree with that. I mean, the takeaway points from the study, really, fluid resuscitation is not one size fits all, so I think it's definitely difficult to protocolize it. We'll move on to the next question, or I will move on to the next question. I'd also really like to know, what endpoints do you use to assess for fluid resuscitation in pancreatitis? A lot of these guidelines cited BUN and hematocrit goals, rather than physical assessment. Sam Kreatnine was cited a few times, so I'm curious to hear what your guys' thoughts are. Okay, 86% said physical assessment, and polling my pharmacist here at Riverside, that's what we ended up with as well. And I would probably do this in my acute pancreatitis patients now, and that is probably not going to change doing physical assessment on those patients to assess for fluid resuscitation. All right, and that concludes my journal club on aggressive or moderate fluid resuscitation in acute pancreatitis. I'll take any questions that you guys have at this time. Just a few questions for you, Shelby. The first one, how was volume overload classified? Were there differences in clinically meaningful volume overload versus lower extremity edema? So volume overload was really classified based off of the pulmonary status. So, dipping below that PF ratio of 300 or requiring mechanical ventilation, there was no delineation between necessarily the outcomes with the different levels of fluid resuscitation. Thanks, Shelby. The next question is, what adverse events associated with fluid overload would you have liked to see reported in this study? That's a good question. I think definitely exacerbation of some conditions like heart failure, electrolyte abnormalities. I would have liked to see, I'm not sure, I can't think of any other ones right now, but those would be the main ones. Pulmonary outcomes, if you were to get fluid overloaded and cause pulmonary edema, incidence of that. Yeah, that's all I can think of right now. I think maybe initiation of renal replacement therapy could have been good to see, too, but I agree. Yeah, but thank you. That concludes our Q&A session. Thanks, Shelby. Thank you. Before moving on to our next presenter, we would like to ask a brief polling question regarding today's attendance to gain a better understanding of our overall attendance to ensure continued support of this Spotlight on Pharmacy webcast. So how many attendees are you viewing this webinar with? Okay, now I'd like to introduce our second presenter, Paige Miller. Thanks so much, Dr. Cascon, for the introduction. Good afternoon, everyone, and thanks so much for joining us. As mentioned, my name is Paige Miller, and I'm the current PGY-2 Critical Care Pharmacy resident at the University of Texas MD Anderson Cancer Center. We will be discussing this recent article published in August of this past year by Zhu and colleagues in BMC Infectious Disease regarding prospective analysis of continuous infusion vancomycin compared to intermittent infusion. To get us warmed up, let's review a few key concepts related to the use of vancomycin. So as a glycopeptide antibiotic, vancomycin is commonly used in the management of gram-positive infections. Therapeutic drug monitoring, or TDM, is often required, and there are two major approaches to TDM, so trough-only monitoring and AUC-MIC. In the trough-only monitoring approach, the target trough is often 15 to 20 milligrams per liter in the treatment of various indications, such as bacteremias, endocarditis, osteomyelitis, meningitis, and hospital-acquired pneumonia, all caused by Staphylococcus aureus. In the area-under-the-curve-over-minimum-inhibitory-concentration, or AUC-over-MIC monitoring, a target is usually about 400 to 600, and it's often reserved for confirmed MRSA or methicillin-resistant Staphylococcus aureus infection. I'd like to pause briefly just for a quick poll with the audience. So at your institution, what's the primary strategy for vancomycin monitoring? Do you use a combination of trough-only and AUC-over-MIC? Do you only use trough monitoring, only use AUC-over-MIC, or some other strategy? Okay, it looks like a majority of you said trough-only monitoring with no AUC-over-MIC, and a close second being trough monitoring and AUC-over-MIC for those confirmed MRSA infections. So I would echo this. So my practice at MD Anderson is pretty similar. So primarily use trough monitoring. However, there are some patients who have confirmed MRSA infection that can extrapolate that AUC-MIC data for. Next, I'll describe some of the background information more specific to the analysis we're reviewing today. So as you are all likely aware, pharmacokinetics can vary widely from one critically ill patient to the next, specifically in the parameters of volume of distribution and clearance. Not only do we see this added complexity in critically ill patients at large, but also the pharmacokinetic and pharmacodynamics of vancomycin are altered specifically in the setting of continuous renal replacement therapy. As a result, vancomycin dosing strategies are a little bit more intricate in this setting. In addition to these changes noted, in 2015, some concerns were raised by Amrani and colleagues with regard to intermittent infusion vancomycin dosing regimens and that attaining PK-PD targets may be a little bit more challenging in the CRRT population. Transitioning into methods and further understanding the inspiration for this analysis, the overarching goal was to compare target attainment, therapeutic efficacy, and safety of vancomycin in patients on CRRT who are receiving either intermittent or continuous infusion vancomycin. The primary outcome examined the attainment of target trough concentrations in AUC over MIC in the intermittent group and attainment of target steady state concentrations in AUC over MIC in the continuous infusion group. The secondary outcomes examined were clinical efficacy, microbiological efficacy, 28-day mortality, adverse events, and correlation of the effluent flow rate to the daily dose with PK-PD indices. The patients included in this study were adults receiving empiric or targeted treatment with vancomycin with acute kidney injury and anurea requiring CBVH or continuous veno-venous hemofiltration. Patients who received concomitant extracorporeal membrane oxygenation or ECMO, they had any changes in the mode of dialysis during treatment or if they had received the first dose of vancomycin therapy six hours or more before the initiation of CBVH were excluded from this analysis. As alluded to previously, there were two distinct dosing strategies utilized in this analysis. The patients in the study were admitted to two independent intensive care units in the Nanjing Medical Center in China. In one ICU, patients were receiving the intermittent dosing scheme and in the other ICU, patients were receiving the continuous infusion dosing strategy. The dosing strategy for these two groups are presented in these blue boxes here. So you'll see the continuous infusion dosing scheme utilized a loading dose of 20 to 25 milligrams per kilogram followed by an initial maintenance dose that was calculated with the equation presented there. This maintenance infusion dose was adjusted per measured steady state levels. In the intermittent infusion group, a loading dose of 20 to 25 milligrams per kilogram was utilized. And the initial maintenance dose was as per the slide. So relevant to the effluent flow rate and all had a frequency of every 12 hours. So either 7.5 to 10 mg per kg, 10 to 13 mg per kg, 13 to 15 mg per kg. And like I said, all based on the effluent flow rate. The maintenance dose for the intermittent infusion group was also adjusted for the measured trough concentration levels. Another brief pause in the presentation for a poll for the audience. So I'm just curious if anyone has any experience with continuous infusion vancomycin. So answer this quick yes or no for me if your institution utilizes continuous infusion vancomycin in CRRT patients. Great. So 97% of you said no, which is kind of what I expected. Thanks for participating in that. And then moving on to discuss the results of the analysis. The baseline characteristics are listed for you here on this slide. The left column of the table denotes the characteristics observed. And as you can see across the top row, we have the intermittent group with 28 patients, the continuous infusion group with 23 patients, and the corresponding p-values. Note that the p-values on the right side had no significant differences between the two groups. So these two well-balanced groups largely comprised a population that was, on average, an early 70s male with a BMI of about 21 kg per meter squared, with an Apache 2 score in the low 20s, SOPA score of about 10, with hypertension, diabetes, and congestive heart failure. A few additional baseline items I felt worth mentioning are highlighted on this slide. The median daily dose was about 21 versus 17 mg per kg. And the median duration of therapy was 8 days versus 10 days. The common sites of infection were pulmonary, bloodstream, and urinary tract. The most common pathogen being MRSA, or methicillin-resistant cephalococcus aureus, and enterococcus fascium. Most isolates also had an MIC of 1 or less. The specific target PK parameters are listed here in the blue boxes above. And the actual attainment of these target concentrations are in the white boxes below. In the intermittent infusion group, the initial mean trough concentration was about 23 mg per liter, with the initial AUC over MIC being about 450. The overall mean trough concentration was about 22.5, with the overall mean AUC over MIC being approximately 394. For the continuous infusion group, the initial mean steady-state concentration was about 20, with the average initial AUC over MIC being roughly 415. The overall mean steady-state concentration was 20, with the average AUC over MIC overall being 410.5. In comparing the two groups, there was a higher likelihood of attaining an initial therapeutic concentration in the continuous infusion group, so 32% compared to 65%, which was associated with a p-value of less than 0.001. With regard to the overall concentration, a similar finding was reported in that patients in the continuous infusion group had a higher likelihood of attaining a therapeutic overall concentration, so 40.5 compared to nearly 80%, with a p-value of less than 0.001. And now for the secondary endpoints. So there were no significant differences reported of particular interest in this analysis. I want to highlight the clinical success in bacterial eradication, as these two items were not different between the two groups. Additionally, the majority of patients in both groups were receiving vancomycin as targeted therapy, as opposed to empiric therapy. The summary items I want to highlight include the overarching finding of this study, which was that Zhu and colleagues demonstrated a difference in the attainment of PK-PD targets for vancomycin therapy in CRRT patients. The continuous infusion group more frequently had target attainment, as opposed to the intermittent infusion group. Additionally, there was no difference demonstrated in either clinical success or bacterial eradication. A few limitations to note. This analysis had a limited sample size of 51 patients, so the study was not adequately powered to detect a difference in mortality. The study was also non-randomized. However, as described in the methods, these patients were two separate groups in two separate ICUs, so when thinking about this logistically, blinding measures may be difficult to employ for these dosing strategies. Some of the PK-PD equations used in the rationale of this analysis did not take into account residual renal function and impact on vancomycin clearance. And lastly, the mode of dialysis used, so continuous veno-venous hemofiltration, cannot necessarily use this to kind of generalize to other common modes of continuous renal replacement therapy. My personal key takeaways and opinion regarding this study is as follows. Better target attainment was demonstrated between these two groups. However, it's hard to weigh the risk versus benefit without adequately powered mortality data. A safety issue I can see occurring here with the use of continuous infusion vancomycin is where CRRT is stopped for any reason and vancomycin continuous infusion therapy is continued by mistake, potentially leading to adverse events and unnecessary, you know, additional nephrotoxicity associated with super therapeutic vancomycin concentrations. Additionally, I'm interested to know a little bit more about how this dosing strategy might impact the workload of nursing staff. While this novel dosing strategy is interesting and the finding is somewhat compelling, future research should address these dosing strategies in larger, randomized, and more diverse with respect to renal replacement therapy mode patient populations. So that concludes my presentation on this article. I hope you enjoyed listening and I'm happy to take any questions you might have. Thanks, Paige. The first question is, did the authors discuss how they handled interruptions in CBVH during vancomycin treatment, or were those patients excluded? Great question. So patients were only excluded if, as I mentioned, if they had received their first dose six hours or more prior to the initiation of CBVH. I believe if CBVH was paused for a certain amount of time that that was reported. But honestly, I'm looking at the article here and I can't find it off the top of my head. But I do believe that they did report it somewhere. Thank you. The second question is, how often do you monitor vancomycin levels in clinical practice? And do you think that continuous vancomycin warrants more frequent therapeutic drug monitoring than intermittent? Great question. So I think in the average patient, vancomycin monitoring should be done anytime there's a dose change and with any associated function or renal function changes, and obviously kind of when instilling a first maintenance regimen. So that's how I would approach a normal patient. But with regard to CRRT and comparing that to IHD, I think the comparison for me would be kind of a risk-benefit analysis, being that patients receiving intermittent hemodialysis often have some sort of chronic underlying renal dysfunction, whereas patients with receiving CRRT might not. So I would say that I would probably want to more intensely monitor patients receiving CVVH. However, I guess I don't really know how that, you know, in practice would change between the average patient who has stable renal function and a patient who has CVVH, if that makes sense. Okay, that will conclude our Q&A session. Thank you, Paige. And now I'd like to introduce our final presenter, Hannah Hixenbaugh. Good afternoon, everyone. My name is Hannah Hixenbaugh, and I am the current PGY-2 critical care pharmacy resident at Cleveland Clinic Hillcrest Hospital. For today's Journal Club, I will be discussing the ADVERT trial and the role of acetazolamide in acute decompensated heart failure with volume overload. The objectives for today's presentation are to review acute decompensated heart failure and current guideline recommendations, discuss previously published literature evaluating the use of acetazolamide in acute decompensated heart failure, and to analyze the ADVERT trial and its clinical applicability to managing patients with acute decompensated heart failure. So heart failure is responsible for over 1 million hospitalizations per year in the United States and Europe and is associated with a 24% 30-day readmission rate. And while the number of agents for the management of chronic heart failure continue to expand, the same cannot be said for the management of acute decompensated heart failure. Acute decompensated heart failure is defined by signs and symptoms of congestion and poor organ perfusion due to heart failure that requires urgent therapy. The most common signs and symptoms of acute decompensated heart failure are directly related to intravascular congestion. And per the 2022 AHA, ACC, HFSA guidelines, it is recommended to use IV loop diuretics, and if decongestion remains inadequate, it is recommended to increase the IV loop diuretic or to add a second diuretic. Prior to completion of the ADVERT trial, the literature evaluating the use of acetazolamide in acute decompensated heart failure was limited to small trials. In 2017, a pilot single-center prospective open-label randomized trial evaluated the impact of acetazolamide on fluid balance. A total of 20 patients were included, and the results and authors concluded that the addition of acetazolamide to a stable diuretic regimen in patients with chronic heart failure resulted in a greater change in fluid balance that was observed by day four therapy. Then, in 2019, an investigator-driven prospective two-center randomized trial evaluated the effect of acetazolamide on natriuresis after 24 hours. A total of 34 patients were included, and the results showed and the authors concluded that the addition of acetazolamide may increase the efficiency of loop diuretics in acute heart failure. So, before we begin the analysis of the ADVERT trial, my first point question is, are you currently using acetazolamide in addition to an IV loop diuretic regimen for the management of acute decompensated heart failure at your institution? So, yes, in almost all patients, only occasionally, only in the setting of metabolic alkalosis, or no, never. So, it looks like most of you are only using it in the setting of metabolic alkalosis, which I think prior to the ADVERT trial, that was kind of how we were using it at our institution as well. So, acetazolamide in acute decompensated heart failure with volume overload, or the ADVERT trial, was published by Mollens and colleagues in the New England Journal of Medicine in September 2022. The trial sought to answer the question, does acetazolamide improve the efficiency of decongestion with loop diuretics in patients with acute decompensated heart failure with volume overload? This study was a multi-center, randomized, parallel group, double-blind, placebo-controlled trial that took place in 27 sites in Belgium from November 2018 to January 2022. Adult patients were included in the study if they were admitted to the hospital for acute decompensated heart failure with one or more signs of volume overload, had an elevated BMP, and were receiving oral diuretic maintenance therapy for at least one month prior. Patients were excluded from the study if they were using acetazolamide maintenance therapy in the prior month or were receiving treatment with another proximal tubule diuretic, which included SGLT2 inhibitors, or if they were hypotensive or expected to require vasopressors. Patients were randomly assigned one-to-one and stratified according to ejection fraction to receive acetazolamide 500 milligrams IV daily or placebo, in addition to a standardized loop diuretic regimen administered as twice the oral maintenance dose. Acetazolamide therapy was continued for three days or until the occurrence of complete decongestion. Treatment escalation was mandated on day two if the cumulative urine output after the first dose was less than 3.5 liters and the signs of fluid overload were still present. The primary outcome of the study was successful decongestion within three days without an indication for escalation of decongestant therapy. Decongestion was assessed using a standardized scale, and complete decongestion was defined as the absence of clinical signs of fluid overload other than trace edema. Secondary outcomes included duration of hospital stay and the composite endpoint of death from any cause or re-hospitalization for heart failure during this three-month follow-up. Safety outcomes included adverse events resulting in discontinuation of therapy, severe metabolic acidosis, renal events, hypokalemia, and hypotension. For the statistical analysis, it was calculated that a sample size of 519 patients would be needed to have 80% power to detect a 10% difference in the primary outcome with a two-sided alpha of 0.05 and account for the potential withdrawal of 5% of patients. An intention-to-treat analysis was utilized, and a linear mixed model was conducted to evaluate the primary endpoint and the duration of the index hospitalization, and a time-to-event analysis with Cox proportional hazard model was conducted to evaluate the composite secondary endpoint, which were summarized with Kaplan-Meier survival curves. A total of 2,915 patients were screened, with 519 patients enrolled. However, four patients randomized could not be assessed for successful decongestion, resulting in 259 patients in the placebo group and 256 patients in the acetazolamide group. Overall, baseline characteristics were similar between the two groups. The average age was about 78 years old, with about 60% of patients, or sorry, about 99% of patients being male. I did want to point out that almost all patients were white, and about 60% of patients had an NYHA functional class of three, and about 30% of patients had an NYHA functional class of four. With 70% of patients having atrial fibrillation. So, looking at our results, successful decongestion occurred in 42% of patients who received acetazolamide, and in 30% of patients who received placebo, which was a statistically significant finding. In a sensitivity analysis of the primary endpoint, excluding the requirement for no escalation of therapy, successful decongestion still occurred in a greater percentage of patients who received acetazolamide therapy. The number needed to treat for the study was nine, meaning that nine patients would need to be treated with IV acetazolamide to have one additional patient achieve successful decongestion within three days. So, the secondary outcomes, the duration of the index hospitalization was an average of 8.8 days in the acetazolamide group, compared to 9.9 days in the placebo group. There was no difference between the groups for death from any cause or re-hospitalization for heart failure. And an exploratory analysis also found that a higher percentage of patients in the acetazolamide group compared to placebo had successful decongestion at discharge. So, looking at our safety outcome results, the incidence of renal events, hypokalemia, and hypotension were low and similar between the treatment groups. And the incidence of adverse events during the three-month follow-up period were similar between the treatment groups. So, from this study, the authors concluded that the addition of acetazolamide to a standardized IV root diuretic therapy in patients with acute decompensated heart failure with volume overload was associated with a higher incidence of successful decongestion within three days. Patients treated with acetazolamide had a shorter hospital stay and were more likely to be discharged without any residual signs of volume overload. And there was not a higher incidence of any adverse events associated with using acetazolamide therapy. So, looking at our strengths and limitations of the study, strengths of the AVER trial included that it was a large, multicenter, randomized placebo-controlled trial that addressed a clinically meaningful question for the management of acute decompensated heart failure. The trial used patient-centered outcomes by evaluating successful decongestion in patients with acute decompensated heart failure. The trial used patient-centered outcomes by evaluating successful decongestion objectively using a standardized scale and followed patients for a period of three months. Limitations of the trial include its limited generalizability. This study was conducted in Belgium and included almost all white patients and did not include any patients who were diagnosed with new heart failure. Additionally, patients were excluded for being on SGLT2 inhibitors, which is now one of the guideline-directed medical therapies. And the initial furosemide dosing regimen was limited to only two times the maintenance dose with a one-time bolus dose and twice daily dosing. Additionally, the study was not powered to evaluate hospitalization or mortality outcomes and lacked quantitative data to evaluate safety outcomes. So, my takeaway point for the study is that in patients with acute decompensated heart failure with volume overload, the addition of acetazolamide to a loop diuretic regimen may increase diuresis and the time to successful decongestion. Based on this study, I think it's reasonable to consider adding acetazolamide early to the decongestion plan. And since the AVRA trial at our institution, we have begun to use acetazolamide more frequently and more early on for the management of acute decompensated heart failure. So, for my last point question, I want to know, how will the AVRA trial impact your use and timing of acetazolamide for the management of acute decompensated heart failure? Not at all. Using it early, like on day one, the late use, day two to three, or late use after more than three days. Okay. So, looking at the results, it looks like some of you, it's not going to impact your clinical progression. And then, for most of us, using it early on within the first few days. So, thank you all for your time today. My contact information is there on the screen if you have any questions. And at this time, I do want to thank you all for your time. So, thank you all for your time today. My contact information is there on the screen if you have any questions. And at this time, I'd be happy to answer any questions that you may have. Thank you, Hannah. The first question is, what is your institution's practice on loop diuretic dosing in heart failure exacerbations? Yeah, that's a good question. And I think that at my institution, it can really vary between providers. There's definitely not a standardized approach that we necessarily take. But I definitely think following the guideline recommendations of using IV loop diuretics at twice the home dose, at least. But there are some providers who may use higher doses. Thank you. The second question is, do you utilize acetazolamide in patients on SGLT2 inhibitors at your institution? Yeah, that's a good question. So, in my experience, I can't say that if I recall using it in any patients on SGLT2 inhibitors, as I feel when these patients are often getting admitted and being managed for acute heart failure, a lot of those home medications are being discontinued. So, I feel like, for the most part, it's being used in patients who are not currently on an SGLT2 inhibitor. But I think it's definitely something that we could consider and wouldn't necessarily stop me from using acetazolamide. But definitely a gap in the literature that could be addressed. Thanks. And then the last question is, what situations would you prefer to use acetazolamide over metolazone? That's a good question. I feel like, at my institution, we mostly are using acetazolamide over metolazone. So, I would honestly not sure, like, in what situation where I would prefer to use acetazolamide over metolazone. If that person wants to email me, I'd be happy to, like, look into it and get back to them. Okay. Thank you, Hannah. That concludes our Q&A session. Thank you to our presenters today, and thank you to the audience for attending. Please join us on the third Friday of every month from 2 to 3 p.m. Eastern Standard Time for the next Journal Club Spotlight on Pharmacy. That concludes our presentation today. Thank you.

critical care

fluid resuscitation

acute pancreatitis

continuous infusion

intermittent infusion

vancomycin

continuous veno-venous hemofiltration

acetazolamide

acute decompensated heart failure