Hello, and welcome, everyone, to today's Journal Club Spotlight on Pharmacy webcast, which is supported by the Society of Critical Care Medicine's CPP section. My name is Atul Dhalwari, a clinical pharmacy specialist working in the cardiothoracic ICU at the New York Vegetarian Hospital of the Columbia University Irvine Medical Center campus in New York. I will be the moderator for today's webcast. A recording of this webcast will be available to the registered attendee by logging into mysccm.org and navigating to the My Learning tab to access the recording. Thank you for joining us, and I want to set up a few housekeeping items before we get started. There will be a Q&A section for each speaker today. 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 us and participate in the live discussion on Twitter, following hashtag SCCMPPJC and also hashtag PharmICU. Before we begin today's presentation, I want to start with a disclaimer. Today's presentation is for educational purposes only. The material presented is intended to represent an approach, view, statement, or opinion of the presenter that may be helpful to others. The view and opinions expressed herein are those of the presenters and do not necessarily reflect the opinions or views of SCCM. SCCM does not recommend or endorse any specific test, physician, product, procedure, opinion, or other information that may be mentioned. And now I'd like to introduce each of our speakers for today. Each will give a 15-minute presentation, followed by a Q&A. Our first presenter is Megan Reddell, a PGY-2 critical care pharmacy resident at St. Luke's Hospital of Kansas City in Kansas City, Missouri. She will be presenting the journal club on low versus standard calorie and protein feeding in ventilated adults with shock, a randomized controlled multi-center open-labeled parallel group trial, the NUTRIA-3 trial. Our second presenter will be Kennedy Cosby, a PGY-2 critical care pharmacy resident at UF Health Jacksonville in Jacksonville, Florida. She will be presenting a journal on propranolol versus amiodarone for supraventricular arrhythmias in septic shock, a randomized controlled trial that was published in Intensive Care Medicine this past year. And for our last presenter, our third presenter will be Cameron Sofia, a PGY-2 critical care pharmacy resident at Stanford Medical Center in Fargo, North Dakota. He will present a large-scale multi-center retrospective study on nephrotoxicity associated with empiric broad-spectrum antibiotics in critically ill patients. And now I would like to introduce and turn it over to our first presenter, Megan Reddell. Hello, everyone. My name is Megan Reddell. I am a critical care pharmacy resident at St. Luke's Hospital in Kansas City, Missouri. And today I'll be presenting the NUTRIA-3 trial, which is evaluating low versus standard calorie and protein feeding in ventilated adults with shock. And this was published in the Lancet Respiratory Medicine of July this year. For a brief bit of background information on this topic, as we know, the benefits of providing nutrition support therapy to critically ill patients really can't be overstated. However, there are many barriers to actually providing this in real-life practice. For one example, patients that may be hemodynamically unstable may require vasopressors, which may put patients at an increased risk for a reperfusion injury when enteral nutrition is provided. As such, there have been studies in the past that have evaluated ways to try to optimize nutrition support therapy despite this. And one strategy that has been described before is using lower nutrition volumes in the acute phase of critical illness. One study in particular that has evaluated this in the past was the EDEN trial, which evaluated initial trophic feeding entropies that they defined as 10 to 20 mLs per hour to full feeding rates that they defined as 25 mLs per hour, advanced the goal as quickly as possible for the first six days of illness. And overall, they found no difference in ventilator-free days or 60-day mortality, but lower rates of vomiting, elevated gastric residual volumes, and constipation, suggesting overall that providing lower rates of feeding in the initial phase of illness may be better tolerated and overall associated with no difference in clinical outcomes. The study did have some limitations, including that it was specific for volume of feeding, so it does leave some questions unanswered of if it was the calories associated with the volumes that led to this outcome, and then also specifically, this was for enteral nutrition. So with that, some hypotheses leading up to the NUTRIA-3 trial were that first, that providing lower calories in the acute phase of critical illness may be better tolerated and have overall neutral clinical benefits, and then at that, too, it's also hypothesized that providing increased protein in the acute phase of illness may lead to more redox reactions, which can actually result in increased muscle weakness and muscle wasting. So overall, the hypothesis of this study was that in critically ill patients receiving mechanical ventilation and vasoactive drugs, of note a patient population that may be at greater risk for intolerance in general, that providing low-calorie and protein feedings may improve clinical outcomes compared to standard calorie and protein feeding. This was a randomized, controlled, open-labeled, parallel-group superiority trial that occurred in 61 franchise youth over about two years, and evaluated the use of low-calorie and protein feedings that they defined as six calories per kilo per day and protein between 0.2 to 0.4 gram per kilo per day, to standard calories and protein they defined as 25 calories per kilo per day and protein between 1 to 1.3 grams per kilo per day, and these were continued for the first seven days of illness, and on day eight, patients were advanced to target calories and protein. Patients included in the study were adults, all receiving mechanical ventilation and vasoactive therapies, which overall they had a pretty limited definition on, but more on that later, but they defined as norepinephrine, epinephrine, or dibutamines, and started within 24 hours of intubation. Patients were excluded if they had long-term, pre-existing enteral or parenteral nutrition needs, if they were more abundant or had other major treatment limitations, to overall, in my eyes, include a pretty general ICU patient population. There were two primary outcomes assessed. The first was 90-day mortality, and the second, a major morbidity endpoint, which they defined as time to readiness for ICU discharge, which included the absence of mechanical ventilation needs, vasopressor needs, delirium, and some other endpoints. There are many secondary outcomes. For the sake of time, I wanted to point out some of the more pivotal ones, in my opinion, first being time to weaning from vasopressors and mechanical ventilation, as this is an outcome that's hypothesized to be improved with providing lower protein, and then also instance of infections, insulin use, and hypoglycemia rates, and gastrointestinal events for major safety endpoints. They did do a power calculation to estimate a sample size to detect a difference before beginning the study, and used mortality estimates based on prior literature, actually, the NUTRIA-2 study, with 43% in standard feeding and 38% in low feeding estimated, respectively. Overall, they estimated a sample size of 3,044 patients would be needed to provide standard alpha and beta rates, and the same power would provide a 94% power to detect a 1.5-day difference in their second primary outcome, which was readiness for ICU discharge. In terms of their primary analysis, 90-day mortality was compared using a chi-square, and time to readiness for ICU discharge was compared using a hazard model, specifically a fine and gray model to be able to control for death as a competing risk. Patients included in the study were pretty standard to what I would expect from a standard ICU patient population. On median, patients were around 66 years of age, about 66% were male with a BMI of around 27. Notably, about 90% were classified as not being malnourished, a little bit more on that later, and about 57, 58% had sepsis as a source of shock, the remainder being cardiogenic or other. Patients had a pretty high SAP2 score in this study as well, about 60, likely due to their mechanical ventilation and vasoactive therapy needs. The study wasn't specific for enteral nutrition, although a majority of patients in the study did receive enteral nutrition in some manner, about 60%, and then about 13% and 19% had parenteral and then were switched to enteral nutrition, and then the remainder had parenteral nutrition. So, again, this study wasn't specific for enteral nutrition, although this is the optimal feeding route, but it does increase the pragmaticity of the study, in my opinion. I wanted to point out, too, something I found interesting in this study, and this is in the supplement, that in my opinion, patients were receiving a pretty high dose of vasopressors with a norepinephrine dose on median of about 0.5 micrograms per kilo per minute. A majority were receiving norepinephrine monotherapy, about 83% and 84%. Very few epinephrine or dabutamine in about 12% and 13% were defined as receiving more than one vasopressor. A little bit more on that later. It's maybe a limitation of this study as well, but just keep in mind for interpreting results at the moment. In terms of their primary outcomes, which were two, 90-day mortality and then time to readiness for ICU discharge, there was not a difference detected statistically in 90-day mortality with rates being about 41% and 42%, but there was a difference detected statistically in time to readiness for ICU discharge, although one could argue not much numerically with the difference being eight versus nine days. As you can see on the curve here, there doesn't seem to be a dramatic difference, although overall, one could argue, too, as a result, that providing low calories and protein may be comparable to providing standard calories and protein as a result. For many secondary outcomes assessed, I wanted to point out these that I thought were a bit more hypothesis-generating. Overall, there was not a difference in time to weaning from vasopressors, but there was a difference statistically in time to weaning from mechanical ventilation, similar to the time to readiness for ICU discharge, with the difference being five versus six days. There was not a difference in ICU infection rates, although it was numerically a little bit lower in the low-calorie and protein group, and also, I would say, not entirely surprising to me, but insulin use was statistically lower in the low-calorie and protein group, and overall, there was not a difference in hypoglycemia rates. So, overall, these secondary outcomes, to me, might suggest that providing low calories and protein, again, while not being associated with differences in their primary outcome, might be associated, too, with lower rates of unnecessary ICU interventions, like insulin use and, perhaps, antibiotic use in the light of lower ICU infection, perhaps, and one less day on a mechanical ventilator, especially, in fact, that the primary outcomes were not statistically significant between groups. At that, too, in the low-calorie and protein group, there were statistically lower rates of vomiting, diarrhea, and bowel ischemia, as well, suggesting, similar to previous studies, which is that low calories and protein might be better tolerated in the acute phase of critical illness, as well. So, kind of similar to as I've alluded to, overall, the authors concluded that early calorie and protein restriction did not decrease mortality, but it was associated with faster recovery, faster time to readiness or ICU discharge, and fewer complications compared to standard calorie and protein targets. Now, when I interpret this study, some first strengths that I appreciate about this study are, first, I think the design is very pragmatic. I appreciate they included a pretty generalized ICU patient population, and I think they assessed many patient-centered outcomes. I particularly appreciate their time to readiness for ICU discharge as a unique primary endpoint, and I think it's definitely clinically significant. And overall, this was a large, multi-center study, which increases external validity. However, some limitations that I think this study could possess are, first, I think bias can't be completely outruled, as it was an open-label study. Patients didn't receive placebo calories, and perhaps some of their endpoints, like bowel ischemia in particular, could have been reported differently between groups. And then, also, some things that I wish I could know about these patients is, perhaps, how many of them received alternative vasopressors. One in particular that I'm curious about is vasopressin, as this is a vasopressor that is associated, perhaps, more so with bowel ischemia, and it's perhaps more controversial with the use of enteral nutrition, and many of the patients in this study were defined as having septic shock, where vasopressin may be used. And then, second, many patients in this study were classified as malnourished, and what was not reported in this study was, perhaps, an M-nutrient score, which is defined in our ASPEN and SCCM guidelines to be used when determining how quickly to advance the goal rates of nutrition, so it's hard to extrapolate these results to other institutions that may use an M-nutrient score to classify the goal rates of nutrition. In terms of clinical application and some key takeaways that I had from this study, first, at my institution, currently, there's no established protocol for nutrition support in critically ill patients requiring hemodynamic or ventilatory support, but there has been some discussion about creating one, and I think this study provides a good amount of data for us to consider in terms of starting nutrition rates or perhaps vasopressor dose cutoffs to consider. At that, too, with their overall primary outcome being no difference in clinical outcomes, I feel more comfortable allowing permissive underfeeding, or if we are concerned for nutrition intolerance, I think this study tells us that, perhaps, using low calories and protein may be a reasonable intervention. And then, going forward, some things that I think to consider for future studies are, perhaps, specific patient phenotypes that might benefit the most from this intervention. Some, in particular, that I am more curious about are maybe patients that may be malnourished as they weren't represented in this study, and I'm curious if providing low calories and protein is still associated with this outcome, or if it might be associated with more harm, or, perhaps, too, patients that might require more support, like, perhaps, maybe burn or trauma patients that have higher metabolic demand. So, I have just a couple polling questions for the audience now to see what other institutions are doing and see some differences in clinical practices. So, my first question is, which of the following best describes your participation and review of nutrition support therapies at your practice site? Do you, A, feel like you manage enteral and parenteral nutrition? B, manage parenteral nutrition macro and micronutrients? Do you, C, manage parenteral nutrition, just micronutrients? Or do you feel that it's not applicable to your current practice site? All right, so it looks like I have the results here, and it's kind of a mixed result. So the majority, 44%, is not applicable to your practice site, and then following that, 40% manage of parenteral nutrition, both macro and micronutrients, with about 12% micronutrients only. And I will say, currently at my institution, we manage parenteral nutrition primarily just micronutrients but can make recommendations for macro potentially. My second question is, which of the following best describes your institution's practices for patients receiving enteral nutrition while on vasopressors, which is perhaps an area of a little bit of controversy? So first, do you feel like enteral nutrition is usually withheld? Do you, B, feel like it's usually held if patients are on more than one vasopressor? C, feel like it's held if patients are receiving more than a certain established vasopressor dose? Do you, D, feel like it's usually started and maintained at trophic rates? Or E, feel like it's usually started and advanced as tolerated without regard to the vasopressor rate? All right, so the results are back. Looks like the majority, 42%, say enteral nutrition, is usually held if patients are on more than a certain vasopressor dose. Kind of like I've alluded to before, currently we don't have this at my institution, but perhaps prior literature may be suggestive of that that higher vasopressor doses may be associated with more intolerance. All right, thank you all for listening. I'm happy to take any questions or comments by the audience now. Thank you, Megan, for that great presentation. So for the audience, if you wanna put your questions in the chat box, and I'm happy to read. Again, that was a great presentation. So you kind of alluded to that this study looked at a general ICU patient population. So in your perspective, do you think these results would be applicable, and you may have mentioned it kind of in your critique, to all types of ICU patients across a surgical patient population, a cardiac patient population, even at the burn patient population. Which specific population do you think that this study, you can apply the results to? Yeah, to me, I feel like overall, well, I feel like it's pretty generalized. A majority had sepsis as a source of shock, about 58%. I believe about 25 to 30% were classified as cardiogenic, and then there are major where other sources of shock. So I would say more so, to me, this probably speaks more of a medical or perhaps a surgical ICU patient population than others. But I think that would be where I feel like this intervention as a result of this study may be most applicable. Anyone have any questions for Megan? I guess I can ask another one, Megan. You kind of also alluded to this in terms of the razor cuts requirements when we get the NARP and epinephrine equivalent of about 0.5 mg per kilo per minute, which again is pretty moderate, a high dose. So when you look at the overall, when you look at the European Society of Clinical Eastern Guidelines, they actually do recommend withholding feeding in patients who are deemed hemodynamically unsafe. So from your perspective and what you kind of saw in this study, how would you kind of refute that argument or kind of go about your practice in managing these patients? Yeah. And I think that's the difference between the European Guidelines and actually our Aspen SCCM Guidelines, which kind of have a vague recommendation similar to, to recommend or to consider withholding in patients that are hemodynamically unstable. But there's also a statement in the guidelines to suggest to consider it if vasopressor doses are declining. So I think overall it depends on the clinical status of the patient and if they seem to be clinically improving. And there have been studies in the past that have evaluated patient populations that aren't vasopressors as a whole and still suggest an overall improvement in outcomes when nutrition is still provided. And I think overall, considering that this study suggests that using lower rates of nutrition and that we're better tolerated and overall associated with no outcomes, if patients that are clinically improving have declining vasopressor requirements, I would feel comfortable allowing a trophic rate overall. Yeah. I totally agree with you. Thank you. Sure. All right. Thank you so much, Megan, for that. And now I'd be happy to introduce our second presenter. It's going to be Kennedy Crosby. Good afternoon, everyone. As Atul said, my name is Kennedy Crosby, and I'm one of the PGY-2 critical care residents at UF Health in Jacksonville. And today I'll be discussing a randomized controlled trial that compared propafenone versus amiodarone for supraventricular arrhythmias in septic shock. Just to give a bit of background, so throughout the years, there's been a growing body of research that's explored the relationship between sepsis and acute arrhythmias, including these supraventricular arrhythmias, so things such as atrial fibrillation, atrial flutter, and paroxysmal supraventricular tachycardia. Namely, patients with sepsis have a six-fold increased risk of developing atrial fibrillation, and that is the most common arrhythmia seen in these patients. The exact mechanism for this really is unknown, but some of the risk factors include advanced age, the presence of other comorbidities, and the severity of the patient's sepsis. Development of the arrhythmias is associated with a longer hospital stay and increased mortality, but there's still conflicting evidence on whether to allow the patient to naturally cardiovert by treating their sepsis or to cardiovert them chemically or electrically. In the most unstable patients, of course, we elect for electric cardioversion to help restore normal sinus rhythm. However, it's usually been found that combining that with an antiarrhythmic can help decrease the risk of recurrence. And for many ventricular and supraventricular arrhythmias, amiodarone remains a drug of choice. In 1991, the Cardiac Arrhythmia Suppression Trial, or the CASH Trial, wanted to test whether the suppression of ventricular arrhythmias with class Ic agents, such as Inconide, Fleconide, and Moricazine, after a myocardial infarction would reduce the incidence of death due to arrhythmia. However, this trial did have to be stopped early due to an increased mortality seen with the Ic agent. However, since then, the conclusions from this trial really have caused hesitation with the use of these agents. However, Balik and colleagues actually challenged the observations in his previous work where he compared amiodarone, propafenone, and metoprolol and found benefit with using propafenone without the increased mortality that was previously seen in the CASH Trial. And that is really the study that paved the way for this prospective trial that I'm going to discuss. Balik and colleagues also wanted to point out how propafenone is structurally more similar to beta blockers than its other 1C counterparts. This chart describes the four Von Williams classifications of antiarrhythmic, their channel and receptor activity, and the clinical effects associated with each of them. We know that our class 1 agents are sodium channel blockers, and they slow myocyte depolarization. And class 1C agents will have the greatest effect. And comparatively, amiodarone is a class 3 agent, and it exhibits the highest action at the potassium channel. However, it does possess other activities as well, such as the sodium, calcium, and adrenergic activities. And so based on this previous work by Balik and colleagues, in this study, he hypothesized that propafenone could perform better than amiodarone in restoring normal sinus rhythms in these patients with septic shock without changing their hemodynamics and possibly even improving their outcomes. So as I said, this was a prospective double-blind, randomized controlled trial, and it took place at two centers in Prague. Patients were included if they were age 16 to 85 years. They had to be diagnosed with septic shock according to the 2016 sepsis 3 definition, which basically was a suspicion of or confirmed sepsis, a lactate more than 2, and the use of vasopressors to maintain a MAP of 65 or higher. And they had to have sustained new onset supraventricular arrhythmia or a known paroxysmal supraventricular arrhythmia as seen on the EKG. There was really no limit on the duration of the arrhythmia before randomization either. The patients were excluded, however, if they had a chronic persistent or permanent atrial fibrillation, and this is usually because the longer an arrhythmia exists, the harder it is to restore normal sinus rhythm. They were excluded if they were receiving high doses of vasopressors, which they deemed as being a dose of norepinephrine greater than 1 mic per kg per minute, and there was no limit on the number of vasopressors a patient could receive. They also excluded patients who were dependent on a pacemaker and those with general contraindications to the use of propafinone, such as a left ventricular ejection fraction less than 35%, a history of AV blocks greater than the first degree. And they also excluded patients with active thyroid disease other than just receiving chronic hormone substitution for benign goiter. And I do want to point out that they did not exclude patients with liver or lung dysfunction. These patients were randomized one-to-one to receive either propafinone as a 70-milligram IV bolus followed by a continuous infusion of 400 to 800 milligrams per day, or amiodarone as a 300-milligram IV bolus followed by an infusion of 600 to 1,800 milligrams per day as rhythm control. There was no limit to direct current cardioversion, and that was indicated if there was a decrease in MAP to less than 70 while a patient was receiving vasopressors, and they did aim for a heart rate between 80 and 110 beats per minute. The primary outcome was efficacy in restoring normal sinus rhythm at four different time points, including 24-hours ICU discharge, hospital discharge, and one-year post-randomization. And secondary outcomes included the rates of direct current cardioversion after these patients were randomized, the recurrences of arrhythmias, administration of an alternative anti-arrhythmic drug, and an ICU and one-year mortality. The power calculation, however, was derived from this previous study by Balik and colleagues, and he found that basically 200 patients would be needed to achieve a power of 80%. And so continuous variables were compared using the Well-Coxon-Ranked Sum test and categorical variables using the Chi-Square Fisher's Exact Test, and the primary and secondary outcomes were analyzed using the Intention-to-Treat principle and the Chi-Square and Kaplan-Meyer curves. There was a total of 209 patients that were randomized to treatment, 104 to the propathinone arm and 105 to the amiodarone arm, and their baseline characteristics are described here. Most patients were age 70 with a moderate Apache and SOFA score. The primary source of sepsis in these patients was the respiratory system followed by intra-abdominal infection, and the median left ventricular ejection fraction was 55%. Then as for the type of arrhythmia that the patients normally presented with, about 75% in each group presented with atrial fibrillation, which was followed closely by about 20% having atrial flutter. And looking at the medications that they were on prior to admission, 20% to 30% of the patients were on a beta blocker prior to admission or inclusion. As for the primary outcome looking at restoration and normal sinus rhythm at these various time points, as you can see here, there was no difference between the groups at any time point. As for the secondary outcomes, there was also no difference in a majority of these, including direct current cardioversion after inclusion, the crossover administration of an alternative antiarrhythmic, or ICU or one-year mortality. However, propathinone did significantly decrease the recurrences of these arrhythmias. And of the patients that did have an arrhythmia recurrence, which was 80 in the amiodarone group and 54 in the propathinone group, the majority of the patients on amiodarone had more than three arrhythmia recurrences, while those on propathinone were more likely to just have one recurrence. The primary outcome was also analyzed in certain subgroups of patients, including those with a left atrial volume index greater than or equal to 40 and less than 40, and those with moderate to severe RV dysfunction. And the study basically found that propathinone performed better in patients who had a non-dilated left atrium or a LAVI less than 40, and amiodarone in those who had a dilated left atrium. But there was no difference between groups in the subgroup of patients that had the right ventricular dysfunction. And so in this, the author concluded that there was no difference between propathinone and amiodarone in achieving the normal sinus rhythm at 24 hours. However, propathinone did decrease the time to achieve normal sinus rhythm and decrease the recurrences of these supraventricular arrhythmias, especially in these patients with a non-dilated left atrium. However, there was no difference in the short- or long-term outcomes. I do think that the study has a few strengths, including its design. It was a multi-center, double-blind, randomized controlled trial. And the primary analysis was based on an attention and treat principle, which I think closely mirrors what we see in practice. And I do think they sought to answer a question that, to date, really has not been answered. However, I do think there are several limitations to the study that are worth mentioning. And so I think the study definitions was a big one for me. Some of them were very unclear, and I felt they were left up for interpretation. So they mentioned that patients were indicated for direct current cardioversion only if they were hemodynamically unstable. However, all of the patients were in septic shock. And so by definition, they were inherently hemodynamically unstable. They also defined the hemodynamic instability as a MAP less than 70 while on vasopressors. But they did not comment on the number of vasopressors that could be present to meet the definition. And we also have to assume that this meant that the MAP had to be sustained, being decreased. But we also have to assume that the patient's vasopressors would have been titrated up in response to that decrease. And kind of in line with that, about 30% to 40% of patients in each group received direct current cardioversion after they were included. There was, again, no limit to the amount of times that a patient could receive this direct current cardioversion. And we can assume that patients may have received more than one, but this information really was not reported. And then additionally, patients who failed rhythm control with one agent could receive a alternative antiarrhythmic or be crossed over. But it's really still unclear if both antiarrhythmics were given at the same time or if either the study drugs was chosen first before an antiarrhythmic of a different class. And so I think altogether, those things really do decrease internal or external validity of the study because I do think it would be hard to reproduce the study without knowing those things. And then also, I just wanted to point out that the basis for the papaphenone dosing is unclear. From what I've found, the doses that we would use or that are usually accepted are much higher than what they used in this study. And so it kind of makes me wonder if we used higher doses in this patient population if we would have seen a greater difference between the groups. So as I wrap up, I really just think the question of whether or not to treat these supraventricular arrhythmias in patients with septic shock remains unclear. As I said earlier, the data on this has still been conflicting. And like I said, this question has yet to be answered. And for patients with a new onset supraventricular arrhythmia without any cardiovascular comorbidities, I think it would be perfectly reasonable to just withhold cardioversion and treat the sepsis. However, I do think that this has to be assessed in a patient-specific manner. However, I just think from the results of this study, I would not change my clinical practice, as I just don't feel the evidence was really robust. And now into my first polling question. Is IV propafinone available at your institution? Yes or no? Okay, this is pretty much as I expected. A lot of those, or the majority, 88%, show that IV progastinone really is not available at your institution. So, I also think that could be a limitation, as even if this data was extremely robust and could have influenced our practice, this is not something that is widely available just yet. And then, as far as the next question, what is the antiarrhythmic of choice at your institution for patients with supraventricular arrhythmias? Is it A, amiodarone, B, progastinone, or C, others? This was also a very expected response. Here at UF Health in Jacksonville, amiodarone is also our drug of choice, so, as I said, this is a very expected. And with that, I will open the floor to any questions. Thank you, Kennedy, for a great presentation. And again, to the audience, if you'd like to ask Kennedy a question, you can put it in the chat, and I can go ahead and read it out as well. So, based on the results of this study, can they actually be applied to all types of supraventricular tachycardia, or are there specific subtypes where progastinone may demonstrate a benefit, not so much for the mortality benefit as demonstrated, but more so for reducing the recurrence and the time to normal sinus rhythm? Is there a specific type of supraventricular tachycardia you can apply this to? I don't think that there is a specific type, especially in this particular study. Most of the patients had atrial fibrillation, so I would say if we would apply it to any subgroup, it would be patients who did not have any structural heart disease, so basically had HFPEF or just normal ventricular function, and who had atrial fibrillation at the onset of their septic shock. Yeah, no, I totally agree. I'm looking at the majority of the patients in this study primarily being AFib, and the concern with using progastinone or your class Ic agent in regards to, if you use it for HFID, there's concern that it could slow the heart rate and lead to reentrant arrhythmias. So, there's more caution in those HFID patient populations as compared to atrial fibrillation, which is not surprising that the majority of the patients were in the study atrial fibrillation. So, that's great. What are your thoughts on, based on the unavailability here in the United States of IV progastinone, would you want to bring it into the, or would you want to, if you had the option to use it here in the United States, the IV formulation, would you be using it in your practice? I think that's a great question. Honestly, I still don't think that we have the answer to the question of whether or not to treat these patients. Like I said, it has to be individualized. And I think, honestly, the study, as well as other studies, just haven't been robust enough specifically for progastinone to say that it would be something that I would prioritize bringing to my institution, at least. Yeah, I think I likewise agree with you. I mean, considering oral use, I believe the study never studied oral, but I don't think that would be something that I would go to over amiodarone, based on these results. So, did the patients receive adequate fluid resuscitation and empiric antibiotics, as well? So, the patients did receive empiric antibiotics, even though they really did not comment on the type of infection, aside from the source. They didn't comment on the bugs that these patients had or what antibiotics they used. And they did receive fluid resuscitation. They actually looked at the IVC collapsibility to determine if these patients were adequately fluid resuscitated. Great. Thank you, Kennedy. It looks like we will move on to our last presenter. So, for our last presenter, I'm happy to introduce Cameron Sophia. Cameron, the floor is all yours. Thank you, Atul. As mentioned, my name is Cameron. I am a PGY-2 critical care pharmacy resident at Sanford Medical Center in Fargo. I am going to be presenting today on the large-scale, multi-center retrospective study on nephrotoxicity associated with empiric broad-spectrum antibiotics in critically ill patients. So, common first-line agents for ICU-status patients are most often going to be combinations of vancomycin with either piperacillin, tazobactam, cefepime, or less often meropenem. I will be referring to these throughout the rest of the presentation as the acronyms I have noted on the slide of VPT, VC, and VM, just for ease of understanding. Evidence of acute kidney injury with VPT has been shown primarily with general medical and mixed patient populations, but however, when it comes to ICU patient populations, evidence has been more unclear as to what exactly the verdict is. There has been several retrospective studies assessing VPT therapy and its historic association with the occurrence of AKI. Primarily, retrospective studies, there's been a mixture of outcomes in terms of association of AKI versus not, and as mentioned, the data primarily comes from general medicine populations. However, in 2022, there was a single-site retrospective study that was completed comparing VPT to other commonly used antibiotic regimens in ICU patients specifically, and this study did show an association with AKI with VPT, as well as in both of their separate components of vancomycin and piperacillin and tazobactam. But it did not, however, show a significant difference in the requirement of renal replacement therapy. The fact that it didn't show an association of an increased clinical outcome, such as renal replacement therapy, suggested at the time that the association with AKI may not have been as clinically relevant as what was once thought. And the study that I'm going to be discussing with you all today was really meant to add to the findings of this single-site study for specifically the critically ill population. And one of the primary reasons surrounding this debate of AKI with VPT involves the well-established occurrence of pseudonephrotoxicity with the use of piperacillin and tazobactam. And this mainly is an effect of the tazobactam component, where it is a competitive inhibitor of creatinine excretion. This competitive inhibition of creatinine excretion in renal tubule cells specifically leads to an artificial increase in serum creatinine without an actual potential worsening in kidney function. And this artificial increase would then lead to the possible diagnosis of acute kidney injury based on diagnostic criteria that uses serum creatinine most commonly to determine presence of AKI. And this mechanism is important to keep in mind while discussing the trial that I'm going to be sharing with you all today. This trial was published in CHESS in August of this year by Chen and colleagues. And the objective of the study was to gain an improved understanding of how AKI risk varies between VPT regimens with VC and VM regimens in the ICU population. The study design was a multi-center retrospective cohort study where data was collected from an electronic ICU Research Institute database and was separated into groups of controls being patients who received VC and VM and exposure group of VPT. And this was done with data collected from ICU stays between 2010 to 2015 across 35 different sites. Only those data was only included if the patients were admitted to the ICU from the emergency department. And this was done in order to get an accurate determination of baseline serum creatinine levels. Patients were excluded if their ICU admissions were under one hour, if they were missing variables pertinent for the outcome or for propensity score matching, if the patient was receiving dialysis prior to the administration of antibiotics, or if they were given more than one of the antibiotic combinations. The primary outcome was the development of acute kidney injury in the first seven days after antibiotic exposure. And this was done based off of the CADEGO guidelines where patients met the primary outcome if they fell into either stage two or three, which I will go into in just a moment here. The baseline serum creatinine was estimated using that lowest serum creatinine value that was recorded while in the emergency department. And it is important to note that only the serum creatinine component was used for determining AKI. And if the patient only qualified for stage one, it was considered a negative outcome. Next, I wanted to briefly discuss the parameters for meeting those CADEGO stages to get a better picture. The Kidney Disease Improving Global Outcomes, or CADEGO organization, has established definitions of three different stages of AKI using serum creatinine and urine output values, which are the most common. The Kidney Disease Improving Global Outcomes has established definitions of three different stages of AKI using serum creatinine and urine output values, which are the most common markers used for monitoring for impaired renal function. Using this table, we can see that the patients would meet the primary outcome for this trial specifically if their serum creatinine was 2 to 2.9 times their baseline or three times their baseline for stage three, or had an increase in serum creatinine to be at or greater than four, or if renal replacement therapy was initiated. Regarding the statistical analysis, Oz ratios and 95% confidence intervals were used for risk assessment of outcomes, and propensity score matching was used between the three subgroups. So for score matching, the control subgroups had considerably less patients compared to the VPT group. And due to this, the control groups were matched to their closest pair in the VPT group, and then all the unmatched VPT patients were not included in the specific analysis. Subgroup analyses were also conducted using baseline estimated glomerular filtration rates with a cutoff of 60 used to define abnormal initial renal function, and also if the patients were on antibiotics for greater than 48 hours. Regarding the demographics of this study, from the diagram, I wanted to note that there was a significantly greater amount of patients, as mentioned previously, who received VPT compared to both VC and VM. If more recent data was taken after 2015, it would likely be that this potentially would not be the case, given a lot of institutions had been changing to more of the VC combination due to the noted association of AKI with the VPT combo. Regarding specific demographics, I wanted to point out a few things. Note that the mean baseline samogreatinine of 1.45 indicates that a majority of patients may have already been developing an AKI due to likely sepsis, given that it was the most common indication for the antibiotics. And the fact that over a third of the patients in the study were obese meant that greater doses of vancomycin would have been required to achieve therapeutic concentrations, although the use of antibiotics was not reported. Higher doses of vancomycin, of course, would have an increased risk for nephrotoxicity alone. In addition to this, the majority of patients had other nephrotoxin exposure, primarily from vasopressors, which would have also affected renal function negatively. In terms of the primary outcome, the three different combinations were compared, both control groups compared with VPT, and I have the odds ratios noted in the bottom right corner for each. The main takeaway from this is that VPT did result in both groups at a higher rate for meeting the KDGO AKI stages 2 and 3. However, I did want to point out that the odds ratio for VM compared with VPT is very close to 1, indicating that the difference found there was close to not being statistically significant, and likely could have been swayed by just a small amount of different outcomes. And regarding the secondary outcomes, do note that there were significant differences in clinical outcomes except for in-hospital mortality. This finding was different compared to the retrospective study that I mentioned previously at the beginning of the presentation in 2022, which did not show a significant difference in these outcomes with VPT. Regarding the subgroup analysis, it was found that the difference in acute kidney injury was greatest in those without preexisting renal dysfunction and patients who received antibiotics for 48 hours or greater, although this confidence interval was by far the largest in the group, and this finding would be really difficult to interpret or apply to practice. The author's conclusion was that there was a greater risk of AKI when using VPT over VC or VM, especially in patients with normal kidney function on admission when requiring antibiotics for greater than 48 hours. In terms of my personal strengths and limitations and thoughts on this trial, regarding strengths, the large data collection sample size is, of course, very beneficial in getting as much data as possible, as well as the strict definition for AKI in this study. Using only stages two and three to meet the primary outcome was the author's way of accounting for that pseudonephrotoxicity that I mentioned earlier with that transient increase of serum creatinine, and this was meant to account for this pseudonephrotoxicity in the results. Additionally, this trial used an ICU population, which could be adequately generalized to other ICU populations requiring empiric antibiotic treatment with appropriate age and indication for sepsis primarily. Limitations-wise, of course, this was a retrospective trial, so no true conclusions can be drawn from it, but more importantly, I think, the use of serum creatinine as the sole indicator for AKI may lead to overdiagnosis, even if only using stages two and three as urine output is a very important clinical measure that needs to be concomitantly evaluated to get a true assessment of renal function. And aside from that pseudonephrotoxicity, serum creatinine may be elevated falsely due to age or presence of muscle tissue breakdown, so it can be very variable and dependent on the specific patient at hand. So, especially in the critical care population, it's something that you cannot take at face value, more times than not. In terms of my personal conclusions, I think that the trial limitations do prevent direct application of results to practice, but do build upon existing literature supporting the association of VPT therapy with AKI. I believe that unless there are concerns for specific bacteria where piperacillin-tazobactam may be preferable compared to cefepime, I feel it's often harmless to the patient to switch from VPT to VC, as there would be no change in overall efficacy or spectrum of coverage. And of course, if there was a concern for enterobacteria, the simple addition of metronidazole would easily cover what would be missed from that switch to cefepime. And with that, I come to my first polling question. So, the question is, your institution actively avoids the use of VPT due to its noted risk of acute kidney injury, true or false? Okay. So, false. That's actually a little bit surprising in terms of, at least anecdotally, from what I've seen. Typically, I have seen providers shy away from using the combination, but I think also it is the idea of that pseudonephrotoxicity starting to gain traction as well. So, there has been some pushback in terms of being able to use that compared to the other combinations. And then for my second polling question is, which antibiotic combination is most commonly seen at your institution for empiric coverage while in the critical care setting? Is it VPT, VC, VM, or a different combination? Yeah. So, as expected, I think there is a pretty even split primarily between VPT and VC. So, VC, just taking a little bit more of the poll. But yes, that result, I would say, is definitely expected for empiric coverage. Okay. I will open the floor to questions. Thank you, Cameron, for that great presentation. Again, for the audience, if you'd like to ask Cameron a question, you can enter it into the chat, and I'm happy to ask it on your behalf. But I guess I'll start off, Cameron, in terms of, when you look at baseline characteristics, they provided a characteristic of percentage of vasopressor use between both of the groups. What more would you want to know in regards to how that may impact the risk of ATI between both of the groups? Yeah, that's a good question. I think it wasn't reported in the study, but I think you would definitely want to know the dose of vasopressors that were being used as well as the quantity in terms of whether it was one versus two or beyond, I think, would be a great indicator in terms of how the use of vasopressors could affect the outcome in terms of acute kidney injury. Yeah, exactly. As you point, didn't know the dose, what's the difference between the two groups. Also, fluid resuscitation, were there differences between that that may impact ATI risk? I guess another question for you, because you mentioned that serum kidney may not be reliable as a marker of ATI given all the confounding variables that you mentioned in critical patient populations. Because this study actually adds to the evidence, how would you redesign this trial to kind of further investigate whether vancomycin, which is a back time cause of ATI in that patient? Yeah, that's a great question as well. I think, truthfully, it would, I think, be a little pretty difficult to kind of redesign this trial in terms of making it better from the standpoint of using serum creatinine as your indicator for acute kidney injury, just because, especially when you're only going solely based off of retrospective data collection, you become very hindered in the sense of like urine output, if you were to analyze data for urine output, it would not be nearly as reliable. And so you would be very hindered by that. And then other options, such as Cystatin C that may be used, would not be reliable as many institutions do not use that as a monitoring tool, given its expense and just inconvenience of using it for common practice of monitoring for renal function. Thank you for that. There's actually two more questions in the audience. So with the recent, first one I'll read out is, with the recent release and results of the ACORN trial that was published in JAMA, that utilized the lab finding as an endpoint in a retrospective trial versus a clinical endpoint like hemodialysis requirement. How would that impact your conclusion or outlook on these findings? Yeah, that's a great question as well. I think it's difficult to balance, right, with the trial that I presented as well as the one in 2022. They both assessed as secondary outcomes. If the, if renal replacement therapy was used in patients and they found conflicting results, so it's hard to say, to imagine what exactly the ACORN trial would have resulted at as well. However, I do believe that it is a very important outcome that you're looking at, especially if given the ACORN trial was not a retrospective trial. But if you are primarily looking at the occurrence of AKI and going solely based off of serum creatinine, as I previously mentioned with the other question, it is very difficult to get a true gauge on the presence of AKI. So having that outcome of renal replacement therapy as your more clinical outcome can definitely back up your conclusion that you may make in terms of whether VPT therapy does or does not perpetrate an AKI. Thank you. And the last question in the audience is, do you think cefepine and nucleic acid would actually change your preference for personal infusal vaccine versus cefepine? I'm sorry, I didn't catch the first part of that question. Would you be able to repeat that? Yes, of course. Do you think that cefepine-induced neurotoxicity would actually change your preference for using cefepine over personal infusal vaccine? I believe that I think it would be primarily patient-independent. I know that the ACORN trial did have that as a finding as well. I think it would be more of a concern, definitely, in like a neuropopulation. If they were to get sepsis, it would require empiric antibiotic coverage. But as far as in the more general patient population and from what I saw with the ACORN trial initially, I would not give it too much thought unless there was an alternate concern backing it up. Great. Thank you so much, Cameron, once again. I want to again thank to all the presenters today and the audience for attending. Please join us again on the third Friday of the month, which is going to be November 17th between 2 to 3 p.m. for the Next Journal Club Spotlight on Pharmacy. This concludes our presentation today. I want to thank again the speakers and the audience for attending, and I hope you all have a wonderful day. Thank you.

Journal Club Spotlight on Pharmacy

randomized controlled trial

low calorie and protein feeding

clinical outcomes

propafenone versus amiodarone

supraventricular arrhythmias

septic shock

faster recovery

nephrotoxicity

broad-spectrum antibiotics