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 is Nicholas Vollmer, Neurosciences and Cardiovascular ICU Clinical Pharmacist at Mayo Clinic in Rochester, Minnesota, and I'll be moderating today's webcast. A recording of this webcast will be available to registered attendees. Log into mysccm.org and navigate to the My Learning tab to access the recording. A few housekeeping items before we get started. There will be a Q&A after each of today's speakers. To submit questions throughout the presentation, type into the question box located on your control panel. You'll also have the opportunity to participate in several interactive polls. When you see a poll, simply click the bubble next to your choice. You may also follow and participate in live discussion on Twitter following hashtag SCCMCPPJC and hashtag PharmICU. Please note the disclaimer stating that the content to follow is for educational purposes only. And now I'd like to introduce your speakers for today. Each will give a 15 minute presentation followed by a Q&A. Our first presenter today is Kelsey Hamlin, PGY-2 Critical Care Pharmacy resident at Prisma Health Richland in Columbia, South Carolina. She will present on the Third Intensive Care Bundle with Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial, or INTERACT-3, an international stepped wedge cluster randomized controlled trial. Our second presenter is Johanna Van Epps, PGY-2 Critical Care Pharmacy resident at UW Health University Hospital in Madison, Wisconsin. She will present on comparative effectiveness of fludrocortisone and hydrocortisone versus hydrocortisone alone among patients with septic shock. And our third presenter is Corinne Whiteman, PGY-2 Critical Care Pharmacy resident at Temple University School of Pharmacy in Philadelphia, Pennsylvania. She will present on pre-hospital tranexamic acid for severe trauma. And now I'll turn things over to our first presenter, Kelsey. Thanks, Nate, for the introduction. Like you said, my name is Kelsey, and today I'm going to be talking about INTERACT-3, which was the intensive care bundle with blood pressure reduction in acute cerebral hemorrhage. So a little bit of background, intercerebral hemorrhage is one of the most serious and least treatable forms of stroke and accounts for around 20% of our 20 million new strokes yearly. Elevated blood pressure is common after the onset of ICH and is also associated with poor outcomes. Currently, acute aggressive reduction of systolic blood pressure has been investigated in numerous clinical trials to reduce the rate of hematoma expansion, as well as death or disability. Currently, hematoma expansion usually is seen most commonly within that first four or six to 24 hours after ICH, and currently the primary recommendation in the guidelines is lowering systolic blood pressure to a target of 130 to 140, and that might be safe and reasonable for improving functional outcomes in patients who are presenting with an acute ICH. So couldn't talk about this trial without going into kind of the background of where this trial came from. So this is kind of a timeline of where our ICH recommendations and guidelines come from. So initially we have in 2003, the INTERACT trial, and this looked at systolic 140 to 150 versus 150 to 160, and this showed that there was a reduced growth in our hematoma volume in patients with that lower systolic blood pressure group. Next in 2007, we had the ATTACH trial, and this had three different groups ranging from 110 to 140 systolic, 140 to 170, and 170 to 200, and there was actually no difference between these groups with regards to three-month mortality rate, neurodeterioration, and also serious adverse events. Next we have in 2013, the ICH ADAPT, and this was systolic blood pressure of 140 versus 162, and this was primarily looking at like ischemic injury following a patient that presents with ICH, and this showed that the perihematomal cerebral blood flow, there was no difference in injuring the tissue when dropping the blood pressure in these groups. Next we have in 2013, the INTERACT-2 trial that came out, and this looked at systolic blood pressures less than 140 versus less than 180 at one hour, and this was also they stopped the blood pressure whenever it went to systolic of less than 130, and this showed that there was no difference in death or major disability at 90 days. Next we have in 2016, the ATTACH-2 trial. This was looking at 110 systolic to 140 within four and a half hours versus a systolic of 140 to 179, and they stopped the blood pressure treatment when the systolic reached less than 110, and this showed that there was no difference in morbidity or mortality, but there were higher rates of neurodeterioration and cardiac-related adverse events in the higher blood pressure group. And then in 2003, we have, that brings us to this current trial, which is the INTERACT-3 trial. So to start off, I wanted to kind of get a gauge of what the audience currently practice in. So first question we have is, what type of institution do you currently practice at? Do you practice at a comprehensive stroke center level one, primary stroke center level two, or an acute stroke-ready hospital level three? Okay, so it looks like majority of our people online practice at a comprehensive stroke center. All right, and then next question I have is, does your institution currently have blood, have a protocol in place for early intensive blood pressure reduction for patients representing with an acute ICD-H? All right, so we're about half and half there of having a protocol already set in place. So we'll present this trial and kind of see what your thoughts are for maybe implementing a protocol. So the objective of this study was to assess whether a goal-directed care bundle protocol comprising of early intensive lowering of blood pressure, also with other management protocols for abnormal physiological variables, and looking at that improved functional outcomes in patients with an acute spontaneous cerebral hemorrhage. So methods of the study, the time period was from May of 2017 to December of 2021, and this was a multi-center blinded endpoint stepped wedge cluster randomized control trial, which is a mouthful. And if any of you are like me, I was not familiar with a stepped wedge cluster randomized control trial. So just to kind of give you a little bit on that, the authors said that they wanted to use it because it would mimic the natural process of rolling out a new quality improvement policy. And so what this entails is having a random and sequential crossover of cluster groups, and these clusters can be anything from hospitals, locations, but those clusters will be randomized of when they will go from the control to the intervention until all of the different clusters have been exposed to the intervention. The study was conducted in nine low middle income countries and one high income country. And then hospitals were eligible to be in this study if they had no pre-existing or if they had no or inconsistent protocols for managing ICH. Inclusion criteria was patients, adult patients with presumed spontaneous ICH within six hours of symptom onset. Exclusion criteria were if the patient presented with an ICH secondary to structural abnormality in the brain or reperfusion therapy. And they were also excluded if the patients were unlikely to adhere to study treatment or follow-up regimen. Looking at the different bundle targets that were in this care bundle, so we have blood pressure and their target was a systolic less than 140, and this was within one hour of treatment initiation. Systolic blood pressure, whenever it reached 130, that is whenever they stopped any kind of treatment. For blood glucose, patients without diabetes, they targeted a blood glucose of 110 to 140. And then for patients with diabetes, they targeted 140 to 180. For temperature targets, we have within one hour of initiation of treatment, a target of 99.5 degrees Fahrenheit or 37.5 degrees Celsius. And then for anticoagulation reversal, they had reversal of abnormal anticoagulation and those who were on an anticoagulation agent using either fresh frozen plasma or PCC with a goal INR of less than 1.5 within that one hour. And all of these targets were maintained for at least seven days following presentation to the hospital. So for outcomes, the primary outcome was looking at functional recovery measured at six months, and this was assessed by the modified ranking scale. And then also we have our safety outcomes, and this was looking at all cause and cause specific serious adverse events. And there were some secondary outcomes, but none of those were powered. So for our baseline characteristics, pretty matched across the board. Average patient was a 61 year old male. And one thing to note is that 87.1% and 91.5 in the care bundle were their ethnicity was Han Chinese. So majority of the patients in the study were Han Chinese. BMI of around 24.1 in both groups. And then also these patients before they came to the hospital with this spontaneous ICH, most of them had an MRS of about 0 to 1. Systolic blood pressure on presentation, the mean was about 174 in both groups. And then the median NIHSS score was about 13 in both groups. One thing to note, too, is also the volume of hematoma that was present in these patients, and that was about 15 in both groups, ranging from anywhere from 7 to 30 mLs. Looking at the different components of our care bundle, so patients with systolic blood pressure less or greater than or equal to 140. This was present in majority of our patients, so 90.2% in the care bundle and 90.7% in the usual care group. Blood glucose greater than 140 in those without diabetes or greater than 180 in those with diabetes. This was present in both groups. Blood glucose greater than 140 in those without diabetes or greater than 180 in those with diabetes. This was present in significantly less, so 34.5% in the care bundle and 37.3% in the usual care. And then we go even further down with our percentages when we start looking at body temperature and then patients with INR greater than 1.5 with only like anywhere from 1% to almost 2% in those groups. So clearly here we see that systolic blood pressure lowering was definitely the main component of this care bundle, especially in this population of patients. So since blood pressure lowering was our focus in this care bundle and where we saw a majority of the data come from, I wanted to focus mainly on that component of the care bundle. So patients requiring IV blood pressure lowering treatment, this was received in 78.9% of patients in the care bundle and 70.9% of patients in the usual care. When looking at the time to reaching target, blood pressure that systolic of less than 140. So we have in the care bundle group 2.3 hours with a range of 0.8 to 8 hours and then in the usual care group we have four hours with a range of 1.9 to 16. And as if you remember from the care bundle group, their target was looking at wanting that systolic of less than 140 within one hour, whereas in this care bundle group the time to reaching target medium was 2.3 hours going up all the way to 8 hours. So for a primary outcome, the likelihood of poor functional outcome was lower in the care bundle group with the common odds ratio of 0.86 and this was statistically significant with a P value of 0.015. So patients who were receiving that care bundle had about an 18% chance of having improved outcomes at that six month mark. I'm looking at the safety outcomes and these were all safety events that were purported and of note these were investigator reported as well. So patients in the care bundle group had significantly fewer adverse events than patients in the usual care group with a number needed to harm of around 24. And patients needed to, so patients need to be exposed in order for one of these exposures of adverse events. I think what's interesting here is that when looking at the adverse events they included everything and the number one reported adverse event was ICH with AKI only being reported in nine patients. So some strengths and limitations of this study is something to talk about. So some strengths of this was it definitely was a large sample size. I mean we had over 7000 patients that were included in the study. You'll see here that stepped wedge cluster design is in both the strengths as well as the limitations. So with it being a step wedge cluster it is a strength because it's going to mimic more of that natural process of how these protocols are implemented into different hospitals. So kind of over time. And also they had a very broad inclusion criteria. Pretty much anyone who presented within six hours were included and only exclusions were if it was like structural deformity that was caused in ICH or from reperfusion therapy. So limitations of this study. So whenever you have a stepped wedge cluster design you have that confounding effect of time. And it's specifically in this study if you look in the supplemental materials there is a chart that kind of looks at when the different intervention and controls. And if you look at the intervention and control there's no overlap between the two whenever you get towards the end of the trial which is kind of expected in a stepped wedge cluster because once you kind of go further on into the trial more clusters are going to be exposed to the intervention rather than to the control. And then also this was during COVID. So having this step wedge cluster where different clusters were introduced to the intervention at different times there was a little bit of delay and they ended up having to extend the study later due to COVID and the different limitations that they had from COVID pandemic. So in conclusion for this study currently the level of evidence for blood pressure recommendation in the current guidelines is a 2B. So would be considered a weak class of recommendation. So maybe from this study we can strengthen that recommendation in the guidelines. Early intensive blood pressure lowering so systolic less than 140 is recommended for all patients who are presenting with acute ICH. I think one thing to think about in this is the generalizability of this study to the U.S. population or the population that you see at your hospital. I know where I work here in the South and South Carolina a lot more of our patients come in with elevated glucose. Majority of these patients that were included in this study were not on antidiabetics at baseline whereas like a majority of a lot of our people are on insulin or oral therapy at baseline. Also in this study patients had a normal most of the patients had a normal BMI. But with the mean being around 24 which is not necessarily the patient population that we see here at our hospital. A small proportion of patients were also on anticoagulation with needed for reversal on presentation which was something that was surprising to me given that a lot of the patients that do come in with these ICHs are patients who are on anticoagulation therapy at baseline whether that be Warfarin or DOAC. So you know when implementing this acute blood pressure lowering after a mild to moderate ICH treatment regimens to limit blood pressure variability and being able to achieve that smooth sustained blood pressure control is going to be beneficial when looking at our functional outcomes. Kind of the key takeaway from this study was implementation of the care bundle protocol for early intensive blood pressure lowering as well as other management algorithms did result in improved functional outcomes for acute ICH patients. So going to our next question based on the trial presented today do you think that bundle care should be implemented at your institution for acute ICH? Thank you. So a little bit of a mix, no, yes, about 22%, no, not against it, but would rather focus on blood pressure lowering, 17% would say further studies are needed, and about 17% of you guys already use but don't care at your institution. And I would have to agree, I think definitely with this study, we saw majority of blood pressure lowering, so I think with the majority saying that you're not against it, but would rather focus on blood pressure lowering is definitely something that crossed my mind. Another thing was, you know, most of the time whenever patients come in, we are managing their blood glucose or reversing their anticoagulation as soon as they come in. So a lot of these things are things that we should be doing whenever our patients are coming into the hospital, into the ED or onto the ICU floors. All right, so with that, we'll take any questions you guys have. Thank you for the presentation, Kelsey. I'll open with the first question here. Did the study report chronic hypertension at baseline for patients, and whether or not it did, do you think that impacts whether or not you should be aggressively lowering blood pressure in such patients? Yeah, so a lot of these patients were, well, it was about 50%, so it was like 44.9 in the care bundle group, and then 42.6% in the usual care group were on antihypertensives before presenting to the hospital. And so I think sometimes these patients are gonna be, are more refractory patients to antihypertensives, especially if they are on them outpatients. So something we might need to be a little bit more aggressive with them rather than, you know, kind of starting more on the lower end, especially because we've seen that blood pressure control is so important in these patients early on. And the second question I had is, obviously, their goal was to get under 140 within one hour, which they were unable to achieve in their intervention group. It seems like they're closer to about 150 in an hour, and it took them about 2.3 hours, as you pointed out. Do you think we should still be striving to achieve less than 140 within one hour, or should we follow what they actually found in the study, which is getting to more about 150 and taking closer to two and a half hours in these patients? I think, personally, I think that the study showed us that it's not hard. I wouldn't say it's not harmful, but the outcomes were not poor in those patients who we did have longer time to achieve or even up to 150. So I think targeting, you know, that goal blood pressure of like 140 to 150 is a good range rather than saying it needs to be less than 140. So I think it just kind of verifies maybe what a lot of us are doing, having more of that goal range rather than targeting specifically less than 140. I still think it's important to try and do it as soon as possible just to prevent that hematoma expansion. Maybe not for people who are extremely high coming in, like over 200, because then we run that risk of kidney dysfunction, which was surprisingly not seen a ton in these patients in the study. But I think it's so important to do it as quickly as possible without dropping it too quickly. But I think having that range rather than targeting specifically less than 140, so like anywhere from 140 to 150. Awesome. Thank you very much. Seeing no other questions from the audience, that will conclude our Q&A session. Thank you very much, Kelsey, for your awesome presentation. Thank you. Before moving on to our next presenter, we would like to ask a brief polling question regarding today's attendance to gain a better understanding of our overall attendance to ensure continued support of this spotlight on pharmacy webcast. Now, I'd like to introduce our second presenter, Johanna. All right, hi, everyone. Thanks for joining today. I will be reviewing the article titled Comparative Effectiveness of Flugercortisone and Hydrocortisone versus hydrocortisone alone among patients with septic shock. All right, so first, just starting off with some background, IV steroids are suggested in patients with septic shock who are requiring vasopressors. Although the optimal dosing strategy and timing of steroid use is not certain, the typical steroid used is IV hydrocortisone at a total daily dose of 200 milligrams, and that can be either given as a continuous infusion or split up over six hours or Q6 hours. The 2021 Surviving Sepsis Campaign Guideline does not provide recommendations regarding the specific use of flugercortisone within this patient population. I did just want to touch on some pertinent previous studies. Some studies have found lower rates of mortality with hydrocortisone and flugercortisone compared to placebo in patients with septic shock. And those would be mainly our 2002 ANANI trial and our 2018 APPROACHES trial. The trials that have looked at hydrocortisone versus placebo have not shown a mortality benefit, and those would be our 2008 CORTICUS trial and the 2018 ADRENAL trial. The 2010 COITS trial did look at hydrocortisone plus flugercortisone compared to hydrocortisone alone, and they did find a difference in mortality that favored the combination hydrocortisone plus flugercortisone group. However, the difference was not statistically significant. And for that reason, the overall comparative effectiveness of hydrocortisone plus flugercortisone compared to hydrocortisone alone in patients with septic shock is less known. All right. So with that being said, that brings us to the overall purpose of this study, which was to answer the question, what is the comparative effectiveness of flugercortisone added to hydrocortisone versus hydrocortisone alone among patients with septic shock? This was a multicenter cohort observational study that included over 88,000 patients, and data was collected using the Premier Healthcare Database, and that gathered patient data between 2016 and 2020. The study looked at patients who either received hydrocortisone alone or flugercortisone and hydrocortisone, and that treatment assignment was based on their initial steroid use, which was based on the same calendar day. The authors conducted a wide variety of statistical analyses, including absolute risk differences with a two-sided alpha value equal to 0.05. They utilized covariate balance calculations, Kaplan-Meier curves, subgroup, and sensitivity analyses. Of note, the authors do disclose that no adjustment was made for multiple comparisons, and for that reason, all analyses outside of the primary outcome should be viewed as hypothesis generating. The study included patients who were admitted to an intensive care or intermediate care unit with septic shock, and patients who received norepinephrine and began hydrocortisone treatment within three days of hospital admission. Of note, septic shock was defined using an ICD-10 admitting code diagnosis, and this has been found to have a moderate correlation with the sepsis-3 definition that many of us are familiar with. The study excluded patients who were less than 18 years old or who had alternative indications for flugercortisone, such as primary adrenal insufficiency, orthostatic hypotension, or congenital adrenal hyperplasia. The primary outcome of the study was composite hospital death or discharge to hospice, and pertinent secondary outcomes include hospital death, vasopressor-free days, and hospital-free days by day 28. Okay, so jumping into some results, as you can see from the table here, for our primary outcome, 47.2 percent of patients in the hydrocortisone and flugercortisone group compared to 50.8 percent of patients in the hydrocortisone alone group fell within our bucket of our primary outcome, which was hospital death or discharge to hospice. This adjusted risk difference came out to be 3.7 percent favoring the hydrocortisone and flugercortisone group, and this was a statistically significant difference. So in summary, there was a statistically significant lower risk of composite hospital death or discharge to hospice in the hydrocortisone-flugercortisone group compared to hydrocortisone alone. Now while I'm on this slide, I do just want to call out, you can see here the different or the amount of participants between treatment arms, and even though over 88,000 patients were included in this study, you can see that almost 86,000 of those patients were within the hydrocortisone alone treatment arm. All right, next, some results for the secondary outcomes or some pertinent secondary outcomes, those being hospital death, vasopressor-free days, and hospital-free days. You can see for hospital death, the adjusted risk difference was found to be 3.7 percent less with hydrocortisone and flugercortisone compared to hydrocortisone alone, and then they found a 0.9 average day increase in vasopressor-free days and a 0.7 average day increase in hospital-free days in the hydrocortisone and flugercortisone group compared to hydrocortisone alone, all of which had statistically significant p-values. In summary, they found a statistically significant lower risk of hospital death and statistically significant higher mean number of vasopressor-free and hospital-free days in the combination hydrocortisone-flugercortisone group compared to hydrocortisone alone. So based on these results, the authors concluded that the addition of flugercortisone was superior to hydrocortisone alone across multiple treatment outcomes, including mortality. Okay, so jumping into some critique or assessment of this study. First thinking about statistical significance, you know, the authors did conduct really robust statistical analyses, but focusing on the primary outcome, the primary outcome was statistically significant as that p-value was less than 0.05. And thinking about the secondary outcomes, although I think the secondary outcomes were clinically meaningful, it's important to recognize that as the author stated, the analysis was not corrected for multiple comparisons. And for that reason, the secondary outcomes were mainly hypothesis-generating. In terms of clinical significance, for that primary outcome, there was a 3% or 3.7% less risk of composite either hospital death or discharge to hospice. The number needed to treat equals 28, meaning we'd have to treat 28 patients in order to prevent one composite of either hospital death or discharge to hospice. Now I think thinking about this 3.7% value and what that means in terms of clinical significance might depend on who you ask or where you practice. But as for myself, from my perspective, based on the limitations that we'll discuss next, this 3.7% number isn't a robust clinically significant difference. But regardless, if you think that this is, that this difference is clinically meaningful or not, I think that it's fair to say that, you know, we know adding flugocortisone would be relatively safe, and the authors do touch on that as well, as they found similar rates of hypernatremia and healthcare-associated infection between the two treatment arms. Moving to the right side of this slide, thinking about the pros and cons, first starting out with some pros. In general, the study did include a large sample size. You know, with over 88,000 patients, the authors were able to gather a lot of patient data using that PREMIER database. The authors also looked at a relevant research question, not only one that is important, but one that has not yet been fully answered by previous studies. Thinking about the cons of this study, first, you know, the study was an observational study, and as we know, with any retrospective study, that comes with inherent risk of bias, as the study is not randomized, and there is risk for unmeasured confounders. The second point here regarding study endpoints, I did want to call out that the authors use a primary outcome of hospital death or discharge to hospice, and even though this is grouped together as a primary outcome, it's important to recognize that these two outcomes are not always one and the same. And then, last but not least, just discussing the study generalizability. So, overall, I think that it's difficult to generalize this study for a couple different reasons. Even though the study included a lot of patient data, I think that without having more specific patient data, or pertinent specific patient data, such as vasopressor doses, what these patients' MAFs were, it's difficult to take these results and learn how to apply it to actual clinical practice. Also, I know I mentioned this earlier, but thinking about the different treatment arms and how there were significantly less patients in the flugocortisone-hydrocortisone treatment arm, that can make us question how are we going to generalize these results, but even more so, why did the patients in the flugocortisone-hydrocortisone group receive both of those medications? And without that information, it makes it difficult for us to know what patients would most benefit from those therapies. And then, last but not least, I did just want to call out the mortality that was seen within this study. Depending on what outcome you look at, it ranged from 40 to 50 percent, and compared to the articles that I referred to earlier, that is a little bit higher. So again, just questioning, you know, why was the mortality higher? Does that signify that there could be unmeasured confounders that are contributing to that number? So to wrap things up here, I think the main takeaway points are that this was a robust multicenter retrospective review. The mortality benefit seen here does further support the mortality benefit that was seen within the previous COITS evaluation, although this outcome was statistically significant. So all things considered, the benefit of flugocortisone remains uncertain. However, these results do provide further insight regarding the treatment of septic shock in critically ill patients. A couple last questions, just to end on here. In terms of anticipated practice change based off of this study, thinking about, you know, the clinical significance and the pros and cons that we talked about, I don't expect to see a full anticipated practice change. However, just with this study coming to light, I think that we might see more use of flugocortisone. For next steps, like any retrospective study, ideally, we'd want a randomized controlled trial, not only to expand on our results, but to really solidify our outcomes. And then last but not least, I think the main question left from this study is, you know, if we do consider that a clinically meaningful difference, what patient population will most likely benefit from that combination therapy? All right, moving into our polling questions. In the setting of septic shock, when do you typically add steroids at your institution? After the patient requires one vasopressor to sustain MAP goal? After the patient requires two vasopressors to sustain MAP goal? Or never? All right, so it looks like mainly, we're adding steroids after a patient is requiring two vasopressors to sustain the MAP goal, and this is similar to what we see at our institution as well. Not only after two vasopressors, but especially if the patient continues to require more norepinephrine requirements at that point as well. And then, moving on into our second polling question. After this presentation, would you consider adding flugocortisone to hydrocortisone in patients with septic shock? Yes. Yes, but only in specific subsets of patients. Yes, I already do, or no? All right, so it looks like we are a little bit split amongst the group. Two most popular answers being yes, in specific subsets of patients, and no. For at least what we've been seeing at our institution, it really has been dependent on the provider. But overall, we've seen a few intensivists added on for patients, but it really just varies week to week. So it'll be interesting to see what the trend is, or what further studies will come out after this trial has been published. All right, and that wraps up my presentation. Happy to take any questions. Thank you very much, Joanna. We have a few from the audience here. The first question being, did you find anything in your background regarding the absorption of oral flutocortisone in septic shock? Oh, that's a good question. I didn't specifically come across that, but I think it's a good consideration for sure. In the background that I came across, they, of course, mentioned that obviously to give flutocortisone, we're going to need enteral access. But beyond that, I didn't come across any specifics regarding its absorption, or how would we take that into consideration? And a second question from the audience. Obviously a lot of statistical wizardry needs to occur for these large population database studies. However, with these results and results of previous studies, what's the downside to adding flutocortisone whenever we start hydrocortisone? What's the downside? You know, I laughed a little bit at the first part of that question, because there was definitely a lot of statistical analyses going on with this trial. But in terms of thinking about the downside, you know, I guess I don't think of any huge downsides offhand, other than we don't have great evidence to support its use at this point. You know, mainly we're seeing the draw for it is having a mortality benefit that we haven't necessarily seen with hydrocortisone. That being said, that's why I think it's important to see, to analyze some of the secondary outcomes like basal pressure-free days, which is, you know, similar data as to why we use hydrocortisone in this specific patient population. But in this trial specifically, we can't necessarily draw those conclusions using its secondary outcomes. So I think overall it's relatively safe to add. I think it would be reasonable. I just don't know if I would necessarily advocate for it myself based on this study and the previous studies. Thank you. And then the last question is, did they report median doses of norepinephrine patients received? Was that median doses of norepinephrine? Yep, norepinephrine. So no, they did not. I don't believe they did. I actually was was searching for that because that was one item that that I thought would be beneficial to use in order to generalize these results. I think that with how they gathered their data using that PREMIER database, they were limited in which patient factors they could pull from that database. You know, it wasn't necessarily the same thing as looking at an EHR. So from what I could tell, they did not. Thank you very much, Johanna, for the excellent presentation. And that will conclude our Q&A session. Now I'd like to introduce our final presenter, Corinne. Thank you for that introduction. And I will be discussing the pre-hospital tranexamic acid for severe trauma trial. Tranexamic acid, or TXA, works to prevent fibrinolysis by stopping the activation of plasminogen to plasmin. Its role in trauma is that it can potentially slow the rapid fibrinolysis seen with trauma-induced coagulopathy. Few guidelines exist regarding the use of TXA in traumas. However, the Western Trauma Association proposes to consider its use when patients are hemodynamically unstable, access to blood products or rapid air transport is unavailable, and there is a concern for potential traumatic brain injury. Similarly, the literature surrounding the different forms of TXA administration show conflicting benefit, which we will now briefly discuss. First, we will discuss the in-hospital administration of TXA. CRASH-2, a trial assessing in-hospital TXA use in trauma patients, found a significant decrease in death rates within four weeks. Additionally, they found that mortality was lower when TXA was given within three hours of injury. CRASH-3, which looked at traumatic brain injury patients, did not find a significant benefit associated with TXA regarding head injury-related death. However, they did find a potential benefit in a subset of patients with mild to moderate GCS scores. In both trials, rates of adverse effects were low, being less than or equal to 2% in all groups and were not significantly different. Moving on to studies which assessed out-of-hospital TXA administration, neither found significant benefits in their primary outcomes, such as 30-day mortality and 6-month functional outcome score. The STAMP trial did, however, find potential lower 30-day mortality in subgroups, such as earlier administration and patients with severe shock. The pre-hospital TXA for TBI study did find increasing rates of thrombotic events with 2-gram one-time doses and placebo compared to the standard dosing. And finally, a previous secondary analysis found increasing rates of thrombotic events with one-time doses of 2-grams or 4-grams versus placebo. Due to the out-of-hospital trials, including mostly patients treated at centers without advanced trauma systems and assessing relatively short periods of time without functional outcomes, the current trial sought to determine if TXA was associated with a benefit in centers with advanced trauma systems and if it was associated with a greater percent of longer positive functional outcomes. Additionally, out-of-hospital administration had not yet shown a clear benefit, but within subgroups such as earlier administration and in severe shock, a potential benefit was seen. In-hospital trials did not find a significant difference in thrombotic events. However, further trials did show increasing risk with increased doses. Due to these conflicting results and potential benefit of out-of-hospital administration within subgroups, the pre-hospital tranexamic acid for severe trauma trial, also known as patch trauma, was conducted. We will now move into discussing the methods and the results of patch trauma. The hypothesis of the study identified by the investigators was that TXA initiated out-of-the-hospital in advanced trauma systems would result in a higher percent of patients surviving with a favorable functional outcome at six months when compared to placebo. They assessed this by conducting an international double-blind randomized placebo control trial across Australia, New Zealand, and Germany from July of 2014 through September of 2021. Key inclusion criteria included being at high risk for trauma-induced coagulopathy, which was defined as a co-score of at least three or higher. Co-scoring is a tool used to identify risk for coagulopathy with elements included as you can see below. Additionally, the first dose of TXA or placebo had to be administered either on-scene or en route within three hours of injury. Key exclusion criteria included known or suspected pregnancy and residing in a facility for older persons. The primary endpoint was survival with a favorable functional outcome at six months, defined as a Glasgow outcome scale extended of five or higher, meaning at least lower moderate disability, which is defined in the included table. This is a validated scale used to extend past typical Glasgow coma scoring looking for longer-term functional status. The primary outcome was further assessed in subgroups defined by age, time to dose, initial blood pressure, type of injury, initial GCS, and the score on the injury scale for heteronec. Secondary outcomes were mortality at predefined time points of 24 hours, 28 days, and six months, and the rate of vascular occlusive events. Patients received either one gram of TXA at the scene over 10 minutes, followed by one gram of TXA at the hospital over eight hours, or the equivalent placebo. A log binomial regression was used to assess the primary outcome, which is typically used to compare the relative risk of a dichotomous outcome, for example here, either achieving a GOSC of at least five or not. This was assessed in both the intention to treat population, which included all randomized patients, and the per protocol population, which included patients who followed through the complete protocol. Now moving into the results, some important baseline characteristics are included for your reference. As you can see, most patients experienced a blunt force injury with greater than 90% in both groups. Most patients had elevated heart rates, systolic blood pressures of less than 90 millimeters of mercury, and a median injury severity score of 29, indicating that these patients represented a severe trauma population. For reference, the injury severity score is calculated by assessing severity of injury across six major regions of the body, typically with scores greater than 12 to 15 indicating major trauma. The primary outcome, which was a favorable functional outcome at six months, was achieved in 53.7% of the TXA group and 53.5% of the placebo group, finding a non-significant difference in the intention to treat analysis. Similarly, a non-significant difference was found when assessed in the per protocol group. Additionally, when assessed in the predefined subgroups, no significant difference was found. You can visually see the breakdown of each group of each level of functional status on the GOSC scale below, with the green-blue colors indicating scores of at least five, meaning the patients reached the primary outcome. Secondary outcomes of mortality at 24 hours and 28 days were lower in the TXA group. When looking at the relative risk ratios, relative risk reductions of 31% and 21% respectively were found. However, at six months, a difference in mortality was not seen. Rates of vascular events, which included DVTs, PEs, MIs, ischemic strokes, and other arterial events were found to be high overall in both the TXA group at 23.6% and the placebo group at 19.7%. For reference, rates of vascular occlusive events in the in-hospital trials, which we had discussed earlier, were less than or equal to 2% in all groups. And in the out-of-hospital trials, it varied trial to trial, but were also lower, ranging from less than 10 total events to near 4% of patients seen with the same dosing scheme used in this trial. The authors concluded that there was no significant difference in the percent of patients with a favorable functional outcome at six months, and that TXA was associated with a potential lower early mortality. Now moving into the discussion of the trial, some identified strengths included that the patient population represented severe trauma patients well. Again, most patients had elevated heart rates, systolic blood pressures of less than 90 millimeters of mercury, and additionally, more than one-third of patients had received blood products prior to randomization. Additionally, the majority of the doses were administered within the three-hour time frame. The GOSC is a validated scale for long-term functional outcome. And finally, in a trial assessing out-of-hospital medication administration, the randomization and blinding techniques were used were strengths, as this can be difficult to control. Some identified weaknesses include a large proportion of patient data lost for the primary outcome, which was mostly due to loss of follow-up. Additionally, a large number of patients experienced protocol deviations. This was mostly due to patients only receiving their first dose. The vast majority of patients experienced blunt force trauma, which reduces generalizability to other areas of the world, where, for example, here at Temple, the vast majority of traumas are induced by penetrating injuries. And finally, a high rate of thrombotic events were found relative to previous studies, which in itself is not a weakness but a result. However, the study lacked a possible explanation as to why this result occurred. Potential areas of benefit of using out-of-hospital TXA identified from this in previous trials could be that a reduction in early mortality was seen. The number needed to treat, despite being exploratory, was relatively low for both 24-hour and 28-day mortality. Additionally, this could be beneficial in areas or situations when time to advance trauma care is delayed. However, giving TXA should not delay time to care, as this has been proven to be beneficial in trauma patients. Some potential cons to using out-of-hospital TXA identified would be that the number needed to treat for the study for long-term functional benefit was found to be 500, meaning that 500 patients would need to receive TXA for one patient to find the defined benefit. Additionally, who can administer out-of-hospital medications, such as EMTs or paramedics, can vastly differ state to state. And for example, here in Philadelphia, only the Philadelphia Fire Department responds to all 911 calls or emergencies, and then this would require universal buy-in of all health systems within the city to implement some sort of protocol of administration. And finally, a very high rate of thrombotic events was found, and there's an unknown risk of giving additional doses. So again, if, for example, when the patient arrives to the ED to the trauma bay, if communication is not clear as to how much TXA they had received, we do not know the associated risks of giving doses beyond what was used in the trial. The trial identified that pre-hospital TXA followed by an infusion did not result in significantly more patients surviving with a favorable functional outcome at six months when compared to placebo. Lower rates of 24-hour and 28-day mortality were seen. However, these can only be assessed as exploratory outcomes. Clinically, this would be difficult to implement as a standard of care, and the findings of the study truly can only be applied to patients with blunt force traumas. A potential use could be scenarios where time to advance trauma care is delayed. However, giving TXA should not further delay time to care. Key points to take away from the PATCH trauma trial include that no significant difference was found in the percent of patients surviving with a favorable functional outcome at six months without a hospital TXA administration. Clinically, it could be reasonable to give out-of-hospital TXA as long as it is not delaying time to advance trauma care and it is feasible to give. At our institution, this trial would not cause a change of practice as TXA is given relatively infrequent in the acute trauma setting and its use varies provider to provider. Potential next steps and further areas of research could be comparing out-of-hospital administration to in-hospital administration of TXA or some sort of pre- and post-analysis after the implementation of a TXA protocol, whether that be in-hospital or out-of-hospital. So now we'll move into a couple polling questions for the audience. So first, to gauge TXA use at your institution, is TXA used either in-hospital or out-of-hospital for trauma patients at high risk for trauma-induced coagulopathy? So either no or infrequently, yes, but on a patient-specific basis, or yes, it is already built into some sort of protocol or the massive transfusion protocol at your institution. Okay, and we see about a three-way split, which kind of mirrors general practice as I've discussed with a lot of our clinical specialists that using TXA seems to be relatively controversial and it kind of varies to every specific institution. So kind of the split that I expected. And then one more question. So what is the most common use of TXA? Next question. So further, is thromboelastography tag or any other viscoelastic assay used to guide anti-fibrinolytic therapy at your institution, either yes or no? Again, kind of a 50-50 split. Again, kind of what I expected here at Temple, we don't really use TAG in the ED trauma situation. It's used further more in the ORs to guide anti-fibrinolytic use. For us, TAG takes about 30 minutes to come back. So when thinking about administering TXA within that three-hour time window, you wouldn't want to use something like TAG to potentially delay time to care. And that is all I have. So I can take any questions that anybody has at this time. Thank you for the great presentation, Corinne. We have one question from the audience. In your opinion, is 28-day death a better endpoint to look at that would be more directly related to TXA administration in a severe trauma? That's interesting. So thinking about the previous trials of like the CRASH-2 trial, for example, where they did find a significant benefit, that was assessing 28-day mortality versus a six-month functional outcome. I do think using something like the CRASH-2 trial, it does support the use of using TXA, whether in-hospital or out-of-hospital. But here, I think the point was to extend past that 28-day mortality mark and look at more of a functional outcome. Because through reading, I've seen that now the thought is more of, in our trauma patients, looking past mortality and looking long-term functional outcomes as they often suffer from pretty severe functional consequences as part of their trauma. So I think looking at 28-day mortality did show benefit, and I do think that's appropriate. But here for this trial, I think they were trying to extend past that and look at functional status at a longer time point. Thank you very much. And then a question I had is, did they do any sort of subgroup analysis within that first three hours in terms of time? Like similar to the CRASH-2, looking within the first hour, and then hours one through three. Did the study look at that from injury to TXA administration? I believe in the supplement they did, and I do believe, again, similar to the CRASH trials, that the earlier the administration provided better benefit. But again, it wasn't a significant difference. It just showed a higher rate. But I think they, again, broke it down by less than an hour, and then within an hour to two hours, and then greater than two hours of administration. Awesome. Thank you very much, Corinne. And seeing no other questions, that'll conclude our Q&A session. Thank you to our presenters today and the audience for attending. Please join us on the third Friday of the month from 2 to 3 p.m. EST for the next Journal Club Spotlight on Pharmacy. That will conclude our presentation for today. Thank you.

Journal Club Spotlight

critical care settings

INTERACT III

functional outcomes

septic shock

early mortality

pre-hospital tranexamic acid

severe trauma trial

clinical practice