Hello and welcome to today's journal club spotlight on pharmacy webcast, which is supported by the society of critical care medicine. CPP section, my name's Joe Mazer. I'm a clinical pharmacy specialist at the Medical University of South Carolina in Charleston, South Carolina. And I will be moderate moderating today's webcast. A recording of this webcast will be available. To the registered attendees, log into my dot org. And navigate to the meeting to the my learning tab to access the recording. A few housekeeping items before we get started. There will be a Q and a section after each of the today's speakers to submit questions throughout the presentation. You could just type it into the question box located on your. Control panel, you also have the opportunity to participate. In several interactive polls with each of the speakers, 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 hash tag, and hash tag. The disclaimer here is just note that the content to follow is for educational purposes only. And now I'd like to introduce your speakers for today. I'm really excited to be doing this. Each will give a 15 minute presentation followed by the Q and a. Our 1st presenter today is Madeline Mitchell. She's a farm. D. P. G. Y. 2 critical care resident pharmacy resident at. You can see Presbyterian hospital in Pittsburgh, Pennsylvania. She will present on to neck to plays versus all to plays in acute ischemic cerebrovascular events. The trace to. Phase 3 multi center, open label, randomized control, non inferiority trial. Our 2nd presenter is Rachel Ballard. She's a farm D. P. G. Y. 2 critical care pharmacy resident at Nebraska medicine in Nebraska. She's going to present on early restrictive or liberal fluid management for sepsis induced hypotension. And finally, our 3rd presenters. Courtney easier farm D. P. G. and P. G. Y. 2 critical care pharmacy resident at Jackson Memorial hospital in Miami, Florida. She's going to present on comparative effectiveness of amiodarone and lidocaine for the treatment. I've been in hospital cardiac arrest and Dr. Mitchell. It's all yours. Hey, thank you so much for that introduction and happy St. Patrick's day. Thanks everyone for tuning in. Today, I'll be thinking about alternatives thrombolytics and acute ischemic stroke. Very briefly, I wanted to review the difference and also place into next place or thrombolytics of interest today is FDA approved for use in stroke has a short. Around 5 minutes, it's less vibrant specific compared to its counterpart. It's dosed as 0.9 milligrams per kilogram with a max of 90. And it is ministered as a 10% as a bolus and then the remaining 90%. Back to place is used off label for stroke has a longer half life of around 20 minutes. It's a bit more specific for vibrant compared to all the place and for stroke. Our dosing is 0.25 milligrams per kilogram with a max of 25 milligrams and is conveniently administered with 100% given as a bolus. Briefly, I wanted to go through some of the trials and data around tenecteplase and stroke, starting with the ATTEST trial. This was completed in 2015, it included 96 patients, and their primary outcome was around reperfusion data. The percent of penumbra salvaged. Okay, so NORTEST1 was completed in 2017, and we used the increased tenecteplase dosing of 0.4 mg per kg compared to alteplase, and showed that tenecteplase was not superior to alteplase with respect to functional outcomes, and it had similar safety data, although this trial did compare patients with smaller strokes and fewer interarterial thrombectomies compared to some of the future trials we'll discuss. EXTEND-IA-TNK was done in 2018, it included 204 patients undergoing thrombectomy, and it showed better reperfusion and functional outcomes that occurred in the tenecteplase group versus the alteplase group, again using our recommended TNK dosing of 0.25 mg per kg. And it also showed no difference in safety outcomes, namely ICH or anterosteoporal hemorrhage. EXTEND-IA-TNK Part 2 was done in 2020, sort of in response to our NORTEST1 trial, and it compared 0.25 mg per kg and 0.4 mg per kg dosing with respect to reperfusion outcomes, and this helped cement our ideal dosing of TNK in stroke. Next in our timeline, we'll talk about Nortest-2. So this was, again, looking at the increased dose of tenecteplase. This was done in 2022. They looked at more moderate and severe strokes with more thrombectomies compared to Nortest-1, and it was actually stopped early due to the increased rate of ICH, or intracerebral hemorrhage, in the tenecteplase group, and therefore led to the abandonment of that increased tenecteplase dose of 0.4 mg per kg and really movement toward 0.25. Lastly, we have the Canadian ACT trial, which was done in 2022, which included 1,600 patients undergoing thrombectomy. Again, they used the 0.25 mg per kg tenecteplase group, and they also found similar rates of good functional outcome between the groups and no difference in their ICH. This, of course, is really only a small snippet of the data. There's been considerable investigation into these two agents for different patient populations and for different dosing strategies, as we sort of touched on, but these trials ultimately led to the creation of the TRACE-2 trial, which is what we will be discussing today, comparing tenecteplase versus alteplase in acute ischemic cerebrovascular events. The hypothesis for TRACE-2 is maybe somewhat predictable based on the studies we've already discussed. They predicted tenecteplase would be non-inferior to alteplase for the treatment of acute ischemic stroke. This was a phase-three multi-center prospective open-lamel non-inferiority trial. It occurred at 53 centers all in China. They used the dosing strategy we previously discussed with the 0.25 mg per kg tenecteplase max of 25 compared to alteplase 0.9 mg per kg. The non-inferiority margin was set at 0.9375, and they calculated 643 patients were needed per group for 85% power. They included adults within 4.5 hours of their symptom onset with good baseline functional status. They had to have mild, moderate, or severe strokes, or moderate to severe strokes, based on the NIHSS scores, and they had to be eligible for thrombolytic therapy based on the Chinese Stroke Association thrombolytic guidelines. These do generally mirror the AHA guidelines as well. They excluded patients who had greater than one-third of the MCA infarcted and those who received or intended to receive endovascular thrombectomy. Authors clarified this criteria in their text by saying these patients were either ineligible for or refused mechanical thrombectomies. The primary efficacy endpoint was functional, modified Rankin scale of 0 to 1 at 3 months. Secondary endpoints involved functional status, improvements in the NIH score, and quality of life. Primary safety endpoint was symptomatic ICH within 36 hours. Secondary safety outcomes of interest were parenchymal hematoma type 2, any hemorrhagic events, and mortality at 3 months as well. As you can see, patients included were around 65 years old, mostly male, and weighed around 65 kilos. They had a baseline NHS score of around 7 in both groups with an onset to needle time of 3 hours, ranging from 2 to 3.5 hours. Notably, around 3.5% of the total cohort did actually undergo thrombectomy, which is one of their inclusion criteria. They also provided cost information, which was interesting perspective in this trial. And then I converted their results into US dollars for our perspective and our reference. You can see the total admission cost for Tenecteplase was around $120 cheaper than that of Alteplase. I did want to pull out and emphasize those characteristics that we use to extend the time window for thrombolytics from 0 to 3 hours up to that 4.5-hour time window that was used for inclusion in this trial. So that's the bottom box there. Around 10% of the total population is greater than 80 years old. A quarter had diagnosis of diabetes, but it wasn't presented in this trial. How many of those patients also had a past medical history of stroke? 1% were already taking anticoagulants. And of course, 0% of their cohort had the NIHS score greater than 25. Without any more info on these patients, and particularly when they presented their past medical history, it's unclear whether or not they may have qualified for thrombolytics in the United States. You can see the breakdown of their primary outcome intention to treat analysis here. The favorable MRS of 0 to 1 at 90 days was achieved by 62% of the T and K patients and 58% of the alteplase patients with a risk ratio of 1.87 and a confidence interval that meant non-inferiority margin. Looking at our secondary and safety outcomes, none of these were statistically significant. However, pH or parenchymal hematoma type 2 was more frequent in the tenecteplase group with a p-value of 0.053. Death was also more common in tenecteplase group, although not statistically significant. From this, the authors concluded that tenecteplase was in fact non-inferior to alteplase for stroke within 4.5 hours of symptom onset. And they stated their support for tenecteplase at the dose of 0.25 milligrams per kilogram as a gold alternative to our standard of care and stated that their trial provided further evidence to support a worldwide switch to tenecteplase for the preferred thrombolytic end stroke. From my standpoint, this trial has a few strengths. They use a lower T and K dose of 0.25 milligrams per kilogram, which is supported by the literature that we discussed at the beginning of the presentation, and it's widely used at these stroke centers in the United States. They also use a primary outcome that was patient-centered and functional at 90 days. However, this study does have a few limitations. Obviously, the open-label design does introduce the opportunity for bias among the clinical staff and treatment teams. They also excluded endovascular thrombectomy patients, which is standard of care in the United States, and it's also recommended for eligible patients in China. This does identify a niche for application of this trial for patients who refuse thrombectomies, but still accept non-surgical interventions, such as thrombolytics, although I'd expect this patient population to be relatively small in the United States. There was no reperfusion data reported at all throughout this trial, and they only reported the rates of PH2, whereas PH1 would also generally be regarded as clinically significant, and H21 or H22 data probably would have been good or helpful to compare to the data that's presented in the other trials. This patient population only included moderate NIH strokes, the median score of 7 up to an upper IQR of 10, which limits its generalizability as well. The authors didn't present any information on the stroke location or the presence or absence of LVO, which, again, would have helped further characterize this patient population and the applicability of this trial. The recurrent stroke rate was not reported in the baseline characteristics as well, which leads us to question whether or not a portion of this patient population would have actually received thrombolytic therapy in the United States. This may have skewed statistical significance over the results, but it's really impossible to tell with the current publication and the data that's been provided. For me, this study helps solidify TNK's role in acute ischemic stroke, and specifically, this data reflects that TNK is non-inferior to alteplase for stroke in patients with moderate NIH strokes who do not undergo thrombectomies. The use of TNK may simplify dosing and administration of thrombolytic and ultimately may lead to, as shown in this trial, modest cost savings. For future directions, the study may open the door for similar studies to be completed in Europe or in the United States, and those patient populations may more closely reflect our patients and usage that we are commonly using in our stroke centers. That leads us to our first polling question. What agent does your institution use for thrombolytic therapy for acute ischemic stroke? Alteplase, tenecteplase, or in the process of switching to tenecteplase? Looks like the majority of our audience uses tenecteplase as we do at UCMC for thrombolytic therapy. Our second polling question, does a pharmacist respond to all condition strokes in your hospital? Yes, only in the ED, only daylight shifts, or no? No. It looks like the majority of our audience does have a pharmacist respond to all condition strokes in their hospital, which is great to see. I think pharmacists have a great role to play here in dosing and helping our nursing colleagues administer this medication as well. With that, I will open it up to questions or discussion. Thank you so much. Really nice job, Madeline. Couple of questions from the audience. Number one question, first question is, based on the limitations of this study and the background literature you presented, which patients would you still prefer alteplase in? Yeah, that's a great question, thanks. I think based on this trial, this obviously has huge limitations in our patient population that's studied here, but based off of the data from the previous trials and sort of the patient populations that were looked at there, I don't have a lot of reservations. Obviously, we have more data coming out sort of further investigating extending the time window of thrombolytics past that 4.5 hour time, which is what is studied in these trials. But that would certainly be a patient population that I would not currently have strong feelings about using at alteplase or tenecteplase. But I don't know that there's a patient population right now that hasn't been investigated with use of tenecteplase. You could argue that patients with LVO haven't had their specific total trial for large strokes, although a lot of this data is sort of extrapolated out of the Xtend IA trial. So I think even though they don't really have their own trial right now, I think extrapolating out from Xtend IAs is what's been done. Great, thank you. What, in your opinion, will it take for tenecteplase to overtake alteplase as the drug of choice in acute ischemic stroke? That's a good question. And I guess my response to that is what evidence do we have to say that it hasn't? I think from the majority of our audience, everyone is, or majority are either using or switching to using tenecteplase. Obviously guidelines don't reflect that right now, but they are outdated. For several years, and we did have an alteplase shortage here that moved a lot of hospitals, I know, at least toward tenecteplase or toward reevaluating the thrombolytic of choice. So I don't know what else needs to happen to move toward sort of a, I guess, a guideline consensus statement toward tenecteplase, but it'd be interesting to see the data that comes out and how the AHA moves forward. Good. How would you convince a manufacturer to make a 25 milligram vial instead of a 50 milligram vial? Kind of a loaded question, but it's a good question. Yeah, that would be super convenient and super helpful. I don't know how compelling an argument is without FDA approval. Yeah. Another one kind of along the lines of formulary management, and probably for you in Pittsburgh and for others is for institutions using this for AIS, is alteplase still on the formulary for non-AIS conditions? Yes, yeah, we do have it. Okay. And kind of along those lines too, from a practical nursing pharmacy perspective, what kind of education have you guys done in your ED or in your critical care units to get people up to snuff as far as using tenecteplase based on its ease of administration and such? Yeah, I think the biggest thing is really emphasizing the difference between alteplase and hospitals that switch and saying like, hey, we're not going to be following the dosing that's probably provided on the package. We're going to be doing 0.25 milligrams per kilogram. I think really emphasizing that point has hopefully reduced dosing errors. And yeah, I think that's pretty much the biggest thing in educating those that are administering this medication. Good. Very nice. Thank you so much. As an attendance poll here, how many attendees are you viewing this webinar with? So, moving on. Thank you, Madeline. Really good. Rachel, Dr. Ballard, Clover's trial, let's go. Thank you for that introduction. I will be presenting on the Clover's trial today. And I have no financial relationships to disclose for this presentation. So, a little background information before we get into the trial. IV fluid resuscitation is a cornerstone of treatment in the management of patients with septic shock and sepsis-induced hypotension. And the 2021 Surviving Sepsis Campaign Guidelines do recommend a 30 mL per kilo IV crystalloid fluid bolus during the initial resuscitative phase of septic shock and sepsis. And the goal of this IV fluid administration is to restore intravascular volume and increase the patient's cardiac output to help with macrovascular as well as microvascular perfusion and reverse any organ hypoperfusion that may have occurred. However, we do know that administering large amounts of IV fluid is not a benign practice and it can lead to adverse effects such as fluid overload. It can induce dilutional coagulopathies and can contribute to organ congestion and overall edema. As an alternative to this liberal IV fluid administration approach, there has been a new alternative approach, which is a restrictive fluid or early vasopressor strategy. And the goal of this strategy is essentially the same as a liberal fluid strategy to increase cardiac output and tissue perfusion. However, we know that vasopressors do have limitations of their own, including tissue ischemia, inducing cardiac arrhythmias, and increasing overall myocardial workload. And so these resuscitation strategies have been compared before in the classic trial, which was published in New England Journal of Medicine just earlier last year. This was a randomized controlled trial that randomized patients with septic shock that were admitted to the ICU to either a restrictive or a standard fluid approach. And ultimately, they found no difference in their primary outcome and several of their secondary outcomes and no difference at mortality at 90 days. So the question still remains regarding fluid resuscitation, specifically in the initial resuscitation timeline. And so in comes QOVERS. QOVERS stands for Crystalloid Liberal or Vasopressor Early Resuscitation in Sepsis. And the authors of this trial really sought to look at sepsis-induced hypotension. Does a restrictive compared to a liberal fluid resuscitation strategy result in lower 90-day mortality? And the authors did hypothesize that a restrictive fluid strategy during the first 24 hours of resuscitation would lead to lower mortality. This was a multicenter randomized unblinded superiority trial conducted at 60 centers in the United States. They included adult patients with either suspected or confirmed infection, and they defined this as administration or planned administration of antibiotics. And they had to have sepsis-induced hypotension, which they described as systolic less than 100, MAP less than 65, or receiving a vasopressor infusion after at least a minimum of one liter IV fluid resuscitation. They excluded patients where an elapse of four hours had occurred since meeting these inclusion criteria. If the patient had presented to the hospital greater than 24 hours ago, if they'd already received greater than three liters of fluids, if they had any presence of fluid overload, such as pulmonary edema, new peripheral edema, fluid overloaded on chest x-ray, or if they had severe volume depletion due to non-sepsis causes. So an example of this would be DKA. And they randomized patients in a one-to-one ratio to a restrictive or a liberal fluid strategy, and they were to follow the study protocol for 24 hours. So just briefly going over the different strategies, the liberal fluid group, if you randomize the liberal fluid group, it was recommended to have an initial two liter IV fluid isotonic crystalloid bolus. This was amended about a year into the trial to limit, or it was okay to limit to a one liter bolus if patients were deemed to be volume repleted after the first liter. And then following that, you were treated, hypotensive, sepsis-induced hypotension was treated with additional 500 mL fluid boluses based on different clinical triggers, which are listed here on the slide, including a MAP less than 65, a systolic of less than 90, a decrease in urine output, or an increase in heart rate. Rescue vasopressors were permitted in the liberal fluid group in the setting of severe hypotension, which is a systolic less than 70, a MAP less than 50, if they had any manifestations of fluid overload, or if the patient had received a total of five liters or more of fluid. In the restrictive fluid group, the prioritized therapy was vasopressors as the primary treatment for sepsis-induced hypotension, defined as a MAP of less than 65 or a systolic of less than 90. Rescue fluids in the restrictive fluid group were permitted for pre-specified indications, such as severe hypotension, severe intravascular volume depletion. And it's also good to note that in either of these groups, rescue fluids and or vasopressors could be administered at any time if the clinical team believed it was in the best interest of the patient. Their primary outcome was 90-day all-cause mortality before discharge home, and they estimated to need a sample size of 2,320 patients for the trial to be 90% powered to detect an absolute between-group difference of 4.5 percentage points, assuming that the liberal fluid group would have an incidence of mortality of about 15%. They used Kaplan-Meier analysis to analyze their primary outcome and had several different pre-specified subgroup analyses, and they used poison regression for their secondary outcomes. And all analyses were used in the intention-to-treat population. Here's the baseline characteristics of the patients in the Clover's trial. So there were 782 patients in the restrictive and 781 in the liberal fluid group. The mean age was, this was a fairly younger patient population, less than 60, 47% female, a mean SOFA score at baseline of about 3.5, and a mean systolic at randomization of about 93. And the time to randomization was fairly quick, within about an hour. And it's also important to note that over 90% of patients enrolled in this trial were enrolled in the emergency department. This figure represents the total IV fluids that were administered to each treatment arm throughout the entire trial. So before randomization, the volume administered was strikingly similar between the two groups with a median of about just over two liters between both groups. But then after randomization initiation of the study protocol, you can see there is a nice diversion between the treatment groups where the restrictive fluid group receives about half as much IV fluids compared to the liberal fluid group at 24 hours. It's also important to note that the most common type of fluid administered was lactative ringers. And this figure represents the total vasopressors administered between the groups. So before randomization, about 18 to 20% of patients were on vasopressors. But then after randomization within the first 24 hours, in the restrictive group, about 59%, and in the liberal group, 37% of patients received vasopressors. And as you can see, the patients in the restrictive group did have quicker time to first vasopressor dose and then longer vasopressor durations, which is not surprising given the study protocol. And the most common vasopressor that was reported was norepinephrine. As far as the primary outcome goes, death before discharge home by day 90, the restrictive group experienced 14% of patients experienced death before discharge home by day 90 compared to 14.9% in the liberal group. So this was not statistically significant. Across all of their different subgroup analyses, they also observed no difference in the primary outcome. And this includes age, sex, location at randomization, baseline SOFA score, and different comorbidities. It is important to note that this trial was halted early at the second interim analysis for futility. So they weren't powered to detect a difference in the primary outcome. As far as secondary outcomes go, they recorded many different outcomes at 28 days, including days free from vent use, days free from renal replacement therapy, days out of the ICU, and days out of the hospital. And as you can see across the board, there is not a difference that was detected between the restrictive and the liberal fluid approach. As far as safety outcomes go, there was also not a difference found in the number of serious adverse offense, in the incidence of ARDS, in the incidence of new onset arrhythmias. And interestingly, the study protocol did allow for peripheral administration of IV vasopressors at least temporarily until a central line could be placed. So in the 500 patients that did receive peripheral IV vasopressors, there was only three reported episodes of infiltration, and all three episodes were reported to resolve without any intervention. The authors of this trial concluded that in patients with sepsis-induced hypotension that were refractory to the initial one to three liters of fluid, a restrictive fluid approach did not appear to improve mortality compared to a liberal fluid approach. Some strengths of this trial, first being a large randomized controlled trial at many different sites in the United States. So this is good external validity if you're practicing in the U.S. However, this could be a limitation if you're not practicing in the United States. The baseline characteristics and fluid resuscitation prior to randomization was very similar between the groups. There was a very high adherence rate to the study protocol. They monitored protocol adherence in the first 300 patients and then in the 10% random sample thereafter, and the adherence rate was about 96 to 97%. There was a distinct separation between the cohorts regarding fluid resuscitation. As you saw on one of the earlier slides where the restrictive group received about half as much IV fluids compared to the liberal group at 24 hours. I listed this as a strength and a weakness, but they utilized non-invasive hemodynamic markers to guide resuscitation. So this protocol could be implemented fairly easily at any institution, which could be a strength. And then I also listed as a strength that they reported on the safety data of the patients who received peripheral IV vasopressors, and only three extravasation events occurred, which suggests that at least temporarily this might be a safe practice in this patient population. Some limitations, first being the unblinded design of the trial, but also taking with a grain of salt that it would have been very difficult to blind this trial, given the large amount of fluids and vasopressors that were being administered to this patient population. The median initial fluid resuscitation between the cohorts and both cohorts was about two liters, but it was anywhere between one to three liters of fluid before randomization. So you could argue that if your patient received three liters before randomization, that that was already considered a fluid liberal approach. There was 1,500 patients that were enrolled in the trial. However, 4,800 were eligible, which means that 3,300 patients ended up being excluded. The most common reason was due to not being able to obtain informed consent. The patient declined enrollment. However, about 26% of the time, it was due to provider preference, meaning that the provider did not want to enroll their patient in the trial. So we have to take this as a little bit of, I guess, we have to understand that there might be some selection bias here. Only 59% of patients in the restrictive fluid group received vasopressors, so meaning that after they received their one to three liters of initial fluid resuscitation, if you were in the restrictive fluid group, only about 60% of the time, you actually received a vasopressor. So this may be due to the patient population just wasn't the septic shock, very acutely ill patients that we sometimes see in the ICU. So it's difficult to know if these results can be extrapolated to that type of patient. The trial was stopped early for futility, so the primary outcome was not power detect difference. Fluid resuscitation was not guided by dynamic measures, so they were mostly guided by systolic blood pressure and MAP cutoffs, which don't really focus on targeting tissue perfusion. They can give you sometimes an idea, but not necessarily very specific. So that could be a limitation of the trial. And it's also important to remember that over 90% of the patients were enrolled in the emergency department within 24 hours of presenting to the hospital. So it can be difficult to extrapolate these results to patient populations that might have a delayed sepsis presentation. So in conclusion, my conclusion from the trial was that a restrictive fluid approach compared to a liberal fluid approach doesn't appear to improve mortality in sepsis-induced hypotension. I think this trial gives us confidence that both of these resuscitation strategies are safe in the early treatment of sepsis-induced hypotension. So given the results of this trial and kind of drawing from historical data with the classic trial where they had a similar design, we now have two trials that are kind of in our arsenal that give us confidence that we do have a little bit of flexibility in the treatment of sepsis-induced hypotension. And this gives us an opportunity to tailor our resuscitative measures to the patient in front of us based on their comorbidities and what their presentation is. So moving on to the polling questions. My first one is, is a fluid restrictive with early vasopressor use or fluid liberal strategy employed at your institution? And the options are fluid restrictive, fluid liberal, or both. And the most common at about 60% was both. And I think that is very representative of what I see as well. I think that providers are very good at tailoring their early sepsis resuscitation to the patient in front of them. And the second polling question, does your institution employ any dynamic resuscitation monitoring, such as passive leg raises, IBC collapsibility, et cetera? And this is either yes or no. And overwhelmingly, yes. So that is great to hear. And the third question is, does your institution employ any dynamic resuscitation monitoring, such as passive leg raises, IBC collapsibility, et cetera? And this is either yes or no question. And overwhelmingly, yes. So that is great to hear. All right. And at this time, I'll open it up for any questions. So you guys got some very good, thought-provoking journal articles here. So here we go in terms of the questions. The first one for you, Rachel, is do you think that it is the limitation that both groups were protocolized and would you have designed the trial differently? That's a great question. So I think that having a protocolized trial like this, it's always difficult because in real life, we don't follow protocols. We don't look at what the systolic is, what the MAP is, and then immediately reach for the vasopressor, immediately reach for the 500 ml fluid bolus. That's just not how medicines practice. So I guess I understand the question. I think one of the things that the authors talk about as their own limitation for the trial is that they wish that they would have had almost a third arm, which is kind of like the real world arm, I guess you could say, of no protocolized practice. But I also understand why they did it. Because when you're designing a randomized control trial like this, it's really difficult to tell providers, okay, you utilize a restrictive protocol and you utilize a fluid liberal protocol. That means different things to different people. So I understand why they did it. But if I were to design it, I think that I probably would have designed it very similarly to the way the authors did and made it more of a protocolized approach, just so it's a little bit more objective. And we're able to draw better conclusions from it. Because when gray areas are involved, I don't think that we would be able to draw similar conclusions from the trial, I guess. Got it. Good answer. Thank you. Was there data on mils per kg versus just mils administered? And could this have had an effect on outcomes in futility? That's the first part of the question, so just try to absorb that. So mil per kg versus just mils, and then outcomes in futility. And then kind of a twofer here with that question is why did they end it early, the paper, the study, when it wasn't really safety data being affected like most trials? They're ended early because they're killing. The intervention is harming patients. In this study, it didn't really look like that. So first question, mils per kg versus just mils, and could this affect outcomes? And then the second one is why the heck did they shut down the trial early? Or what are your thoughts on that? Yeah, so for the first part, the mils per kg, I had the exact same question as you. I have been looking for if they define it in mils per kg because, I mean, like you are kind of alluding to, the surviving sepsis campaign guidelines recommend a 30 ml per kg IV fluid bolus, so we should probably be looking at this in a weight-based sense, excuse me. And so I had the same question. And I couldn't find any report of that in the supplementary index I was kind of looking through. I couldn't find it. So if you found it, please let me know. But I didn't see that they reported it in mls per kg. And then for the second part of the question, the stopping early for futility, I guess I'm not sure why I would, if I were to venture a guess why they stopped it early, despite no decreased safety outcomes, I would guess the cost of the trial would be my guess. But I guess I don't know for sure why it was stopped early. But if you look in the supplementary index, the Kaplan-Meier survival curves, they're just like right on top of each other, like it wasn't going to show a difference, which is, I think, why they ultimately decided to halt the trial. Good, very good answers. That trial, I mean, there was a lot, our center was involved. It took a lot of, it was a lot of time, you know, a lot of study coordinators, a lot of time to even enroll these patients, like probably more so than most trials, you know, starting in the ED and carrying over to the critical care setting. So final question, given the low mortality rate, you would not think that these patients meet traditional septic shock criteria. What do you think of this new category of patients, sepsis with hypotension, who would not have traditionally received vasopressors? Yeah, I think that that is one of the, I think I listed that as one of the limitations of the trial. So I think that, so the patients met, like, I guess, general sepsis criteria where they had a dysregulated response to an infection and they had hypotension, but they didn't necessarily meet the septic shock criteria. And that wasn't necessarily an inclusion criteria. You didn't have to be defined as septic shock. They just had, if you were sepsis with hypotension, persistent hypotension, excuse me. So I think that it kind of limited the patients that were in the trial. Like, I feel like we were looking at both septic shock patients and just patients with sepsis. So I feel like if we maybe looked at specifically septic shock patients, we would have seen a lot more vasopressor use rather than the 60% that we saw. And therefore we can maybe, and maybe if we were utilizing the strategy in sicker patients, maybe we would have seen a difference. I, that I don't know. But yeah, the sepsis-induced hypotension definition was a little bit, it was new to me. So I thought it was very, an interesting choice. And I thought the systolic blood pressure cutoff was also an interesting choice of less than 100. Because theoretically, you could have a patient that had a systolic of 98 or 99 and maintained a MAP of greater than 65. And then they wouldn't need any hemodynamic support. They wouldn't need vasopressors, which we saw in about 40% of the time in the restrictive group. Well, good answers to those questions. Thank you for your presentation. Really appreciate it, Rachel. For our last cleanup hitter, Dr. Gieser will be doing our third journal club. We're looking forward to this. Dr. Gieser, she comes from Jackson Memorial Hospital and she's gonna be looking at the comparative review of lidocaine to imiodurone for in-hospital cardiac arrest. Yes, thank you very much for the introduction. As you said, my name is Courtney. I will be reviewing a trial conducted by Wagner that was released last year to compare imiodurone versus lidocaine for in-hospital cardiac arrest. To provide a brief review of the current ACLS guidelines before we jump into the trial, the VTAC and VFib cardiac arrest algorithm is listed here. As we know, the preferred first-line treatment would be a shock of the VTAC or VFib rhythm followed by epinephrine and either imiodurone or lidocaine for the antiarrhythmic of choice. As we see in the box to the right, the imiodurone dose would be 300 milligrams for the first bolus followed by 150 milligrams for the second bolus. For the lidocaine dose, it is one to 1.5 mix per kick for the first dose and 0.5 to 0.75 mix per kick for the second dose. These guidelines by the American Heart Association were created based on out-of-hospital cardiac arrest trials that did not show a difference between imiodurone compared to lidocaine for out-of-hospital cardiac arrest. The trials that did support adding lidocaine onto the guidelines in addition to imiodurone were based on trials that only focused on out-of-hospital cardiac arrest patients. But as we know, there are about an equal amount of patients that do have a cardiac arrest in the hospital versus out of the hospital. And there are limited studies that do evaluate the use of antiarrhythmics in adult patients with in-hospital cardiac arrest. There are many patients to the factors that differ between in-hospital and out-of-hospital cardiac arrest, specifically the risk of out-of-hospital cardiac arrest being unwitnessed and delaying time to CPR and antiarrhythmic therapy. So it's unknown if these strong trials for out-of-hospital cardiac arrest may be extrapolated to our patients that do have arrest in hospital, or if there are future trials that would support the use for either imiodurone or lidocaine for in-hospital cardiac arrest. To briefly review these guidelines that have supported the change for ACLS to add on either imiodurone or lidocaine for VTAC or VFib cardiac arrest, the first trial is Dorian, and that is a live trial. They compared imiodurone to lidocaine for patients with VFib out-of-hospital cardiac arrest. They noted that imiodurone had a significant increase in survival to hospital admission. The next trial is the Roth-Elf trial, and they also compared imiodurone and lidocaine to placebo as an adjunct to VFib relation for VTAC and VFib out-of-hospital cardiac arrest. They did not overall find a difference between imiodurone and lidocaine when compared against each other for out-of-hospital cardiac arrest. Upper lidocaine compared to placebo was significant for increased rates of Roth, whereas imiodurone versus placebo did not have a significant difference. These last two trials are in-hospital cardiac arrests that were conducted in the early 2000s. They were conducted with around 100 patients, so it did have a limited sample size as well as a retrospective chart review, so it may have some limitations as well. They compared imiodurone and lidocaine for in-hospital cardiac arrest, and they did not find any significant differences between these two agents for in-hospital cardiac arrest. That takes me to this study, and this study really wanted to evaluate the difference between these two agents for in-hospital cardiac arrest using a larger sample size than the previous study. It was a retrospective cohort study that was conducted within a registry with American Heart Association, it was a guidelines resuscitation registry. This registry is a national multi-center prospective registry and quality improvement program for in-hospital cardiac arrest. Hospitals have submitted an online case report form for patients that do have an in-hospital cardiac arrest where they are able to submit medication history, hospital care, and outcomes using this online case report form. This study evaluated registry data submitted from January 2000 to December 2014. To analyze the data from the registry, they used independent group T-tests for continuous variables and Chinese squared analysis for binary variables. They did include patients with an in-hospital cardiac arrest and received either Imiodarone or Lidocaine. So they excluded patients that received both antiarrhythmic therapies because they really wanted to identify if one agent did provide improved outcomes over the other. As the guidelines do suggest defibrillation prior to receiving any epinephrine or antiarrhythmic therapies this study did exclude patients who did not receive defibrillation, so the patients that did not follow the ACLS algorithm. They wanted to evaluate the outcome of BRASK in these patients, including the secondary outcomes of 24-hour survival, survival to hospital discharge, and favorable neurologic outcomes using the CPC or the cerebral performance category, which is listed on the right. They defined cerebral performance category as favorable for patients that either had a CPC of one or two, which would either be up to full or moderate disability, and considered as non-favorable for the patients that did have a severe disability to death. During the timeframe, they did identify around 40,000 patients that did have data submitted from the registry, and these were in-hospital cardiac arrest patients with BTAC or BFib. They excluded the patients that received both amiodarone and lidocaine, and also received the patients that did not receive defibrillation. So they identified 14,630 patients that did meet the inclusion criteria. Around a third of patients were treated with lidocaine, and two-thirds of patients were treated with amiodarone. To compare the baseline characteristics, the demographics were very similar between the groups. However, the pre-existing conditions did differ significantly between the two groups. Overall, the patients in the lidocaine group did have lower rates of pre-existing conditions compared to the amiodarone. Specifically in the box that we see here, the lidocaine group had lower rates of diabetes, hepatic and respiratory insufficiency, and septicemia. Because it was a registry data or study as well, we did also have limited information, including the primary reason of hospitalization, if the patient was on any antiarrhythmics prior to cardiac arrest, and the etiology of the cardiac arrest. When we look at the results of the registry on the different outcomes, there was no difference between the lidocaine and the amiodarone groups on ROCK. However, the secondary outcome, as listed below, did show a benefit, including the higher rates of 24-hour survival with lidocaine, survival to hospital discharge, and favorable neurologic outcome. So it did show a benefit with the secondary outcome. Because there was a significant difference in baseline characteristics, specifically with comorbidities of lidocaine to amiodarone, the authors did conduct statistical analysis to account for these differences in characteristics at baseline. So they used both multivariate modeling and propensity score methods to compare two different statistical analysis and see the difference in outcomes when adjusting for these covariance. They did identify that when adjusted, lidocaine did have a benefit in all of the outcomes compared to amiodarone. So lidocaine did end up having a benefit in ROCK compared to amiodarone, in addition to the secondary outcome. To evaluate this study and provide my feedback on this study, so there were observational findings in this study that did find a benefit of lidocaine over amiodarone, but it was retrospective. So a prospective review would really limit the confounders and limit any bias associated with this study. Even though the authors did adjust for variables in the baseline characteristics, they were not able to fully eliminate the bias of confounders. So having a prospective study would hopefully limit some of the confounders to a greater amount. There was also data limited because it was a registry study. So we don't fully know the reason why providers may have reached for lidocaine over amiodarone in these patients. For example, the patients, we do not know the primary reason of hospitalization, the hospital arrest etiology and the CPR duration. And finally, we do not know the total amount or the dose of antiarrhythmic that was administered because it was not reported. So there is concern that perhaps the patient did not receive an appropriate dose of the antiarrhythmic and perhaps that that's why there was a difference seen in the outcome. Specifically with the previous studies that I reviewed and also anecdotally, I have seen that providers may not administer the correct dose of the amiodarone. For example, the vial comes in 150 milligrams dose so that providers may reach more towards giving one vial at once instead of taking two vials and drying it up in a larger syringe. So it could be a concern that amiodarone did not show a benefit over lidocaine simply because the dose was not appropriate. But like I said, we do not know for sure the dose that was used in these patients. In summary, this was the largest study to date that was evaluating antiarrhythmic use in adult patients but in-hospital cardiac arrest. As we said, the current ACLS guidelines simply focused on out-of-hospital cardiac arrest because this is where we have the most data. But we do know that there are different patient specific factors that may influence the outcomes in our patients if they do have a cardiac arrest in-hospital versus out-of-hospital. This does have results that were opposite compared to the previous in-hospital cardiac arrest trials that were smaller, that did not show a benefit of lidocaine over amiodarone. Conversely, this trial does show support for lidocaine over amiodarone and it does have appropriate clinical endpoints of ROSC and mortality. In addition, it is a very large and multi-center trial. It had over 14,000 patients, so it was a very large sample size. Next steps would be having a prospective trial to really limit the confounders and then also identifying the impact on this study on future ACLS guidelines within the future ACLS will make alternative recommendations for in-hospital versus out-of-hospital cardiac arrest. Finally, I have a couple of polling questions to assess the current practice at your institution. My first question is, what percentage of the time is lidocaine chosen as a first-line antiarrhythmic for in-hospital VTAC or VFib cardiac arrest at your institution? And I see that the majority of institutions reach for imiodurone over lidocaine, which I would say is very expected. In my limited experience, typically lidocaine is used when the patients fail imiodurone. So very expected that imiodurone is typically preferred over lidocaine, first line. My last question is, does your institution have lidocaine levels resulted in-house? And this is a yes-or-no question. And it looks like that the majority of institutions do not have lidocaine levels resulted in-house, which is similar to Jackson. My thought is that perhaps providers are more willing to reach for lidocaine boluses in cardiac arrest if they are able to have appropriate monitoring for a drip. For example, at Jackson, we do not have lidocaine levels in-house, and it does take five days for lidocaine levels to result approximately. So, providers are less likely to jump for a lidocaine infusion because of the concern that patients may be not appropriately monitored just due to the fact that we do not have lidocaine levels in-house. So, that may be a reason why some providers reach for a lidocaine bolus over an aneodrine bolus simply with available labs that we have. These are my references, and I would be happy to answer any questions. We got a few coming up, so get ready. First of all, do you think, based on the trial size, that this is going to alter practice? You know, as a large cohort of patients, retrospective, do you think that this could influence lidocaine being a preferred agent over amiodarone, or do you think it's too much in the past as far as when the study was conducted? That's a good question because this was conducted in the early 2000s, and in 2018 was when we have the updated guidelines with amiodarone or lidocaine. So, I would say that it is very retrospective, and a prospective trial would be needed. I don't believe that this would provide enough support to sway providers from choosing amiodarone or from choosing lidocaine over amiodarone, but in the patients or the providers that do choose lidocaine first line now, it does provide further support for that, but I don't think that it would really change providers' minds if they typically go for amiodarone first line. Okay, good. Kind of along the lines of that question, based on this study and others, do you think there were any subgroups that could be teased out that you would advocate using lidocaine over amiodarone or a preferred agent in a hospital cardiac arrest? I think that one of the largest limitations of this trial was the lack of data that we were unable to get, simply because it was a registry trial. Specifically, the patients that were on antiarrhythmic therapy prior to cardiac arrest, I think that that probably had a big factor for why providers chose lidocaine over amiodarone. Specifically, if a patient was previously on mexilatine prior to the cardiac arrest, maybe lidocaine would be a good option for them, or if they were previously on amiodarone and had a cardiac arrest on amiodarone, maybe choosing lidocaine to have an alternative therapy. I'd say that a subgroup analysis of a patient previously on antiarrhythmic therapy would be very valuable to compare lidocaine versus amiodarone. Okay. A couple more questions. What are the major pharmacologic differences, or are there any, between lidocaine and amiodarone that you would prefer one agent over the other? And would this study alter your practice? Like, would you choose lidocaine over amiodarone? So, two for a gain. Pharmacologic differences between lidocaine and amiodarone, and what would make one think theoretically it could be preferred? And then, what would you do? Or what would this change? That's a good question. I would say that the biggest difference that comes to mind to me for amiodarone versus lidocaine is the risk for toxicity is greater with lidocaine versus amiodarone. So, it is much easier for providers to monitor amiodarone therapy and be less concerned about toxicity because we do not need levels for that versus lidocaine. We would have to get a level after 24 hours on an infusion. I would be concerned about toxicity associated with lidocaine. So, I would say that typically providers would prefer amiodarone just due to the fact of toxicity associated with lidocaine and the need for monitoring. And then, I would say based on this trial, I would not change my practice. I would say that amiodarone is usually used first line, but lidocaine may be easier to use during a code because it does typically come in a prefilled syringe. So, it may be easier to administer for the nurse if there is a chance that I don't have syringes available, for example, and would need something immediately for the patient. But I wouldn't say that this would really influence me strongly to choose lidocaine over amiodarone in all patients in hospital cardiac risk. Good. And last question. What are your thoughts on the differences in the baseline characteristics in both groups in terms of the amiodarone group maybe being sicker than the lidocaine group? Yes, I definitely do think that that may have influenced the outcomes, even though they did adjust for the covariance, that there was still a chance that the lidocaine did show a benefit in the primary and secondary outcomes simply because the lidocaine group was less sick compared to the amiodarone. So, I definitely think that that was a major limitation of this study as well. And with differences in baseline characteristics. Great. Thank you very much. Thank you. I'd like to complete this and conclude this Journal Club presentations. I want to thank our presenters today, Dr. Mitchell, Ballard, and Gieser. You guys did a great job. And I want to thank the audience for attending and their participation. Please join us. The third Friday of the month would be April 21st. Another Journal Club spotlight on pharmacy from 2 to 3 Eastern next month. And that concludes our presentation today. Want to thank everybody and happy St. Patrick's Day.

journal club spotlight

pharmacy webcast

teclaplace

alteplase

stroke

fluid management

sepsis-induced hypotension

amiodarone

lidocaine

in-hospital cardiac arrest