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 Brennan Herman, a surgical ICU pharmacist at the University of Mississippi Medical Center in Jackson, Mississippi. I will be moderating today's webcast. A recording of this webcast will be available to registered attendees. You can log in to MySECM.org and navigate to the My Learning tab to access the recording. A few housekeeping items before we get started. There will be a Q&A after each of today's speakers. To submit questions throughout the presentation, type into the question box located on your control panel. You will also have the opportunity to participate in several interactive polls. When you see a poll, simply click the bubble next to your choice. You may also follow and participate in live discussion on Twitter following hashtag SECMCPPJC and also hashtag PharmICU. Please note the disclaimer stating that the content to follow is for educational purposes only. And now I'd like to introduce you to our speakers for today. Each will give a 15-minute presentation followed by a Q&A. Our first presenter today is Jordan Holmeyer, a PGY-2 critical care resident at Corwell Health West Hospital in Grand Rapids, Michigan. She will present on inhaled amicacin to prevent ventilator-associated pneumonia. Our second presenter is RJ Mendoza, a PGY-2 critical care pharmacy resident at VA San Diego Healthcare System in San Diego, California. RJ will be presenting on ceptobiprol for treatment of complicated staphylococcus aureus bacteremia. And our final presenter is Madison Koons, a PGY-2 emergency medicine critical care pharmacy resident at the Massachusetts General Hospital in Boston, Massachusetts. She will be presenting on early and empirical high-dose cryoprecipitate for hemorrhage after traumatic injury. And now I'll turn things over to our first presenter. Oh, gosh. Okay. Well, hello, everyone, again. I'm Jordan Holmeyer. I'm a PGY-2 critical care resident at Corwell Health West in Grand Rapids, Michigan. And I'll be presenting on inhaled amicacin to prevent ventilator-associated pneumonia. Here are just some abbreviations I'll be using throughout the presentation. Amikin-Hall will be the biggest one, and that is the shortened name of the trial that I will be presenting. Just some objectives for the presentation. I'll be reviewing background of ventilator-associated pneumonia, analyzing the results of the Amikin-Hall trial, and then discussing the clinical implications of this trial. Firstly, let's go through some backgrounds. So hospital-acquired pneumonia is the most frequent presentation of hospital-acquired infection of the lower respiratory tract. The estimated incidence varies depending on things like the definition, screening methods, and patient populations from 2 to 30 episodes per 1,000 days of mechanical ventilation. And the disease develops in 5 to 14% of intubated critically ill patients. The mortality of this disease can be up to 13%. And then also with this disease state, it comes with increased antibiotic exposure, duration of mechanical ventilation, increased length of stay, and increased cost. To date, there's been many different standards that have been implemented to prevent ventilator-associated pneumonia, including but not limited to things like reduced sedation and weaning protocols, head-of-the-bed elevation, sterile handling of the tracheal tube cuff, and importance of oral care. One area recently that has been looked into is inhaled antibiotic therapy as a preventative measure. Inhaled antibiotic therapy enables delivery of very high antibiotic concentrations to the tracheal tree, lung parenchyma, and tracheal tube biofilm. There is a meta-analysis of six different trials that looked at inhaled antibiotics to prevent ventilator-associated pneumonia and suggested efficacy of this. And so this is where this trial comes into play, looking at inhaled amikacin to prevent ventilator-associated pneumonia. So this brings me to the first polling question. Do you believe we undertreat or overtreat ventilator-associated pneumonia within the ICU? Yes. So as a pharmacist, I think that we do overtreat ventilator-associated pneumonia within the ICU, exposing patients to increased antimicrobials, maybe increasing their duration of mechanical ventilation. So I kind of expected this answer. So today, I'll be evaluating this journal, the Inhaled Amikacin to Prevent Ventilator-Associated Pneumonia. It is an investigator-initiated, multi-center, double-blind, randomized, controlled superiority trial comparing inhaled amikacin to placebo. This was a trial that was conducted within 19 ICUs in France between the timeframe of July 3, 2017 to March 9, 2021. They had patients receiving 20 mg per kg times ideal body weight once daily or placebo for three days. All patients were eligible for enrollment if they had undergone invasive mechanical ventilation for at least 72 hours. They were not eligible for enrollment after 96 hours of invasive mechanical ventilation or if they had suspected or confirmed ventilator-associated pneumonia. Also if they had a severe acute kidney injury without renal replacement therapy or had chronic kidney disease based on their GFR. This is the assessment and randomization. So from July 3, 2017 to March 9, 2021, they had a total of 6,419 patients that were assessed for eligibility and 850 patients were ultimately enrolled. This left 420 in the amikacin group and 430 in the placebo group. They did have three patients withdraw informed consent, which decreased the amount to 417 in the amikacin group and 430 patients in the placebo group. Most of these patients in the trial received all three scheduled nebulizations. About 337 patients or 81% in the amikacin group and 355 patients or 83% in the placebo group. The mean amikacin dose in the amikacin group was about 1,625 milligrams and then nebulized over 47 minutes and in the placebo group 13 mLs of sodium chloride was nebulized over 49 minutes. Their primary outcome was a first episode of ventilator-associated pneumonia from randomization to day 28. This required a positive quantitative bacterial culture in the pulmonary sample and at least two of the following findings, so hyperleukocytosis, leukopenia, fever, or purulent secretions with a new infiltrate on a chest radiograph. I'm not going to go through all the secondary outcomes, but major ones that they looked at were number of days of mechanical ventilation from randomization to day 28 and they also looked at mortality at day 28 and day 90. So for statistics, they estimated that in the expected incidence of ventilator-associated pneumonia of 6% in the amikacin group and 12% in the placebo group, those statistics they found that they needed a sample size of 850 patients and that would provide the trial with 80% power to show efficacy with a two-sided alpha of 0.05. The analysis were performed according to the intention-to-treat principle and the threshold for statistical significance was set at 5% and two-sided 95% confidence interval were calculated for all estimates. Here are some of the baseline characteristics. The characteristics of the patients at randomizations were pretty well balanced between the groups and are considered to be representative of the target population. Of note, at the time of randomization, 78% of the patients were receiving systemic antibiotics. Bringing us to the results portion, here is the graph that shows the results of the primary outcome of a first episode of ventilator-associated pneumonia with inhaled amikacin or placebo from randomization to day 28. With the placebo or the blue line, you can see that there was a higher incidence than that of the inhaled amikacin group in this trial. This is another table of all the results that they found. So at day 28, days of follow-up, the first episode of ventilator-associated pneumonia, so the primary outcome had developed in 62 patients or 15% in the amikacin group and in 95 patients or 22% in the placebo group. The difference in restricted mean survival time to ventilator-associated pneumonia was 1.5 days, and this was statistically significant. The first episode of ventilator-associated pneumonia after randomization occurred at a median of 10 days after randomization in the amikacin group and at nine days after randomization in the placebo group. And then you can see in the last rows there that the median number of days on mechanical ventilation was even between the groups. This is a continuation of the secondary outcomes. Length of stay and mortality was similar between both groups, and then a serious adverse effect that was considered by central review to be related to the trial occurred in seven patients in the amikacin group and in four patients in the placebo group. Among the patients who did not have an acute kidney injury at the time of randomization, an AKI developed by day 28 in 11 patients in the amikacin group and 24 patients in the placebo group. This is those secondary outcomes just put in graphs, so panel A, or the one all the way to the left, is the cumulative incidence of ventilator-associated conditions. The middle graph there is infection-related ventilator-associated complications, and then the one on the right is possible ventilator-associated pneumonia based on the definitions framework for ventilator-associated events. The widths of the confidence intervals in these graphs have not been adjusted for multiplicity and should not be used to reject or accept the treatment effects, but you can see in all three that inhaled amikacin did better than the inhaled placebo. This trial did have some strengths. It was a very large trial. There were some limitations. It was only powered to investigate the primary outcome, so we can't really take any of the secondary outcomes and make conclusions with them. Seventy-eight percent of the patients were already on systemic antibiotics by the time we started amikacin, so do we really know it was the amikacin that prevented the ventilator-associated pneumonia? We used sodium chloride as placebo, which also could be an infection risk in the placebo group. The primary outcome definition included having to have positive sputum results. In the ICU, a lot of clinical pneumonias are treated without these positive results, so are we really getting the numbers of ventilator-associated pneumonia in this trial? And then the estimated 12 percent of incidents for VAP used to control for the calculation of the sample size was smaller than the trial where the incidence was found to be 15 percent versus 22 percent of ventilator-associated pneumonia. So the study's conclusion was that a three-day course of amikacin at a dose of 20 milligrams per kilogram of ideal body weight is effective in reducing the risk of ventilator-associated pneumonia. The results were consistent with other ventilator-associated events, were consistent regarding ventilator-associated events, and then less than two percent of the patients had a serious adverse effect in this trial. So this brings me to polling question number two. Do you think inhaled amikacin should become standard of practice in preventing ventilator-associated pneumonia based on this study alone? No. That's kind of what I figured, and if we go on to the next slide, my conclusions ultimately are that the primary outcome may not reflect the true number of pneumonias if they were requiring that positive sputum culture. Length of mechanical ventilation was the same between both groups, so is there any real clinical significance in reducing the incidence of VAPs that was shown? And then broad utilization of inhaled antibiotics in the ICU setting can lead to resistance patterns. So ultimately, I came to the same conclusion as the audience here. I would not recommend making prophylactic amikacin a standard of practice to reduce VAP based on this study alone. And that brings me to the end of my presentations. Here's some additional resources I used, and I am open to take any questions at this point. And I was curious, do you feel like this is, I guess, as far as application, do you feel like redesigning of this trial that they could have done to maybe shown that there would be benefit of inhaled amikacin, or do you feel like this is kind of not a pointless feat? That is a good question. I think it's hard to decide a ventilator-associated pneumonia trial, looking at all the different factors that can cause a VAP. I think it would be hard to convince anyone to do inhaled antibiotics to prevent a ventilator-associated pneumonia. So I don't know a specific redesign of the trial that would convince me that we should start doing inhaled antibiotics. Okay. Thank you so much. That's going to conclude our Q&A session. Okay. Now I'd like to introduce you to our second presenter, RJ Mendoza. Thank you so much, Brennan. So good morning or good day, everyone. My name is RJ Mendoza. I am a PGY-2 critical care pharmacy resident from VAC San Diego, and I'm here to present about my journal club entitled Sefto Biprole for Complicated Staphylococcus Aureus Bacteremia, also known as the ERADICATE trial. So at the end of my presentation, I would like for you all to be able to first review the diagnosis and treatment for bacteremia, second to analyze the results of the recently published ERADICATE trial from the New England Journal of Medicine, and last is to evaluate the use of Sefto Biprole in clinical practice and where does it fall in the treatment algorithm for MRSA bacteremia. All right. So let's begin. When we talk about bacteremia, we define it as the viable bacteria in the blood. So whether we have bacteria present in the blood, it's also known as BSI or bloodstream infection. We have two types of bacteremia. We have asymptomatic and symptomatic bacteremia. Meaning there is no clinical, it's a clinical benign infection, whereas symptomatic is patient will have symptoms and if not intervened appropriately, which can lead to severe complications. In terms of sources, bacteremia can be caused by a lot of things. It could be from lines, drains, procedures. It can also be caused by underlying infection from all over the parts and organs of the body. So it could be seeded from meningitis, endocarditis, osteomyelitis. It could be from septic arthritis, pneumonia, UTI, skin and soft tissue infection, as well as psoas abscess. So that is why once our patients become bacteremic, we definitely need to intervene right away. In terms of signs and symptoms, patients typically present with fever, chills and rigors within the first 24 hours. And then if not appropriately treated, it could lead to more severe symptoms such as hypertension, altered mental status, tachycardia, which could lead to septic shock. So this is the clinical progression from bacteremia to ultimately death without any intervention. So from bacteremia or bloodstream infection, it becomes sepsis because patients will present with systemic symptoms of infection. If there's end organ damage or organ dysfunction, it can lead to septic shock. And furthermore, again, if we don't manage patients, it can lead to other complications such as endocarditis, acute renal failure, meningitis, ARDS, which can ultimately lead to death. In terms of MRSA bacteremia, so this is a specific type of bacteremia that is caused by MRSA or methicillin-resistant staphylococcus aureus. In terms of the incidence, it is one of the most common causes of bloodstream infection. In fact, the incidence of MRSA bacteremia happens in about 50 cases per 100,000 patients. The mortality in developed countries, despite antimicrobial therapy and source control strategies, the mortality is still around 20 to 30%. But in developing countries, the mortality can go up to as high as 70%. In terms of prevalence, MRSA in staphylococcus aureus isolates is actually more prevalent, greater than 50%. That is why in terms of empiric therapy, we typically start patients that are presenting with bacteremia and septic-like picture with an anti-MRSA agent as a broad spectrum empiric therapy. In terms of diagnosis, bacteremia can be diagnosed with blood culture and echocardiogram. Very clinically significant isolate is staphylococcus aureus. That's why we're discussing it today. But there are also other bacteria that can cause bacteremia. Other gram positives include streptococcus species, enterococcus species, as well as other gram negative microorganisms such as E. coli, Klebsiella, Enterobacter, and Pseudomonas. In terms of echocardiogram, it is recommended by the guidelines that adult patients with bacteremia should get some form of echo. TTE, or transthoracic echocardiogram, is usually performed first because it is minimally invasive and more convenient to perform as opposed to TEE, which is preferred. However, it is a little bit more invasive and requires a specialist to do it. In terms of pharmacotherapy, we have three FDA-approved treatment options for MRSA bacteremia based from the guidelines. We have vancomycine, second is daptomycine, and recently, last month in April, Ceftobiprol was just approved by the FDA for bacteremia caused by MSSA and MRSA, as well as SSDI and other indications. In terms of vancomycine, we try to target the goal of the dose 15 to 20 mg per kg administered every 8 to 12 hours depending on trough of 15 to 20 or AUC over MIC between 400 to 600. For daptomycine, the dose that we typically use is 6 mg per kg IV every 24 hours, although some experts will use a higher dose, 8 to 10 mg per kg IV every 24 hours, especially in cases of persistent bacteremia or complicated bacteremia. And last, for Ceftobiprol, which is the topic of our discussion today, the dose is 667 mg IV every 6 hours for 8 days, then switch to every 8 hours thereafter starting from day 9. So the 667 mg is actually the Ceftobiprol-medocaryl salt form, which is equivalent to the Ceftobiprol base form, which is dose 500 mg. So again, if you see 667 mg, that is the salt form, it is equivalent to 500 mg of the active Ceftobiprol base. The duration of treatment for bacteremia is typically, if it's uncomplicated, it is at least 2 weeks, but for complicated or persistent bacteremia, it's typically between 4 to 6 weeks. We also have other treatment options for MRSA bacteremia, even though they are not FDA-approved for this indication, but we use them based on the activity. We can use linazolid, we can use ceftaroline, which is also another 5th generation cephalosporin, we can use trimethoprim, sulfamethoxazole, or Bactrim. We can also use clindamycine and dalvavancine. Doxycycline can be used only for community-acquired MRSA infection. All right, so this brings me to our trials for today, the ERADICATE trial, which was published in the New England Journal of Medicine in October of last year. This was from the ERADICATE study group, headed by Holland et al. So, the ERADICATE trial is a phase 3, multi-center, double-dummy, double-blind, non-inferiority, randomized controlled trial. The main objective of this trial is to determine the safety and efficacy of ceftabipro in treating complicated staph aureus bacteremia and comparing it with standard-of-care daptomycin. For the active drug, ceftabiprol, this is a new generation extended-spectrum cephalosporin. Just like your ceftaroline, it has activity against gram-positive and then gram-negative, especially MRSA activity as well. So, the study intervention, so what the authors did, they compared the active drug, ceftabiprol, 500 mg IV Q6 for 8 days, then Q8 thereafter. Again, you can see 500 mg, that is the active base form of the drug, which is equivalent to 667 salt form. They compared it against daptomycin, dose between 6 to 10 mg per kg IV Q24, with or without astreonam, as per gram-negative coverage. The ceftabiprol group, they have a matching placebo, so if patients receive two infusions, the analyst or the researchers don't know which one of this, because it's a double-blind study. In terms of the criteria, they included hospitalized adult patients that have a confirmed staph aureus bacteremia based on a positive blood culture within 72 hours prior to randomization. The patients, they included patients must have at least one of the following signs and symptoms of severe or systemic infection. So, temperature greater than 38 degrees, white count greater than 10,000 or less than 4,000, heart rate greater than 90, and systolic blood pressure less than 90. Patients also are included if they have other complications, such as osteomyelitis, septic emboli, SSTI, and right-sided endocarditis as well. In terms of exclusion criteria, they excluded patients who have received an anti-staphylococcal antibiotics within 48 hours or greater than 40 hours within 7 days prior to randomization, except when they failed to clear the bacteria, so they needed more treatment. Also, they excluded patients with confirmed uncomplicated staph aureus bacteremia, including patients with unremovable vascular prosthetic material and pneumonia. So, the definition of complicated bacteremia that they use in the trial is defined as a persistent positive blood culture despite antibiotic therapy greater than 3 days, staph aureus associated with long-term hemodialysis, and also present of other complications that we just discussed. So, the endpoints that they use for primary, they use the overall treatment success at 7 days after randomization, which they actually define as survival, symptom improvement, bloodstream clearance, absence of any complications, and no other use of other antibiotics. Whereas for secondary endpoints, they use death from any cause, microbiological eradication, or basically a clearance of the culture, as well as time to bloodstream clearance and adverse events for safety. So, this is what they've done. So, once patients are eligible for enrollment, they randomize them to 1 is to 1, 1 receiving the active drug and the active comparator daptomycin. Patients can receive the treatment for up to 42 days, and then the researchers assess the primary endpoint based on day 70. Day 70 is just a random number that they chose, because by then, all of the infections should be resolved. Again, the trial is powered to assess primary endpoint, but not the secondary endpoint. In terms of study participants, the baseline characteristic is a median age of 58 years old. Majority of them are from Eastern Europe, 93%. The median duration of antibiotic administration is 21 days, so around 3 weeks. Only 11% of patients receive a dose of daptomycin greater than 7 mg per kg. However, patients in both groups receive a matching placebo or AstraZeneca around one third of the patients. In terms of the complications of S. aureus bacteremia, over 60% of them are from the soft skin and soft tissue infection. Of note, only around 25% of the patient population have a confirmed MRSA staph or MRSA bacteremia. What did the researchers find? They found that in terms of overall success, they actually found that they are not statistically significant. So, 132 patients in the ceftavipril group was treated successfully, compared to 136 patients in the daptomycin group, so around 69% in both. In terms of secondary outcome, it's also non-significant when it comes to death from any cause, microbiological eradication, and new complications. In terms of adverse effects as well, in terms of safety, it is also not statistically significant. A lot of the adverse events are from GI, such as nausea, vomiting, diarrhea, and sometimes some electrolyte abnormalities, such as hypokalemia, and some changes with their taste of the patients. But very few serious adverse events, around close to 20%. So, if we look at the forest plot of all the subgroup analysis, they actually found that ceftavipril is actually better. It's favored as a treatment for MRSA bacteremia. However, again, it's not powered to detect a secondary outcome, only the primary outcome. So, what the authors concluded is that ceftavipril was non-inferior to daptomycin with respect to overall treatment success in patients with complicated staph aureus bacteremia. In terms of the strengths and limitations, the ERADICATE trial actually compares ceftavipril against an active medication, so standard-of-care daptomycin, which is a good thing. It is a large randomized controlled trial, multi-center trial in 60 sites in 17 countries. However, the majority of them are in Eastern Europe. And in terms of consistency, the results were actually consistent in all subgroups. Very minimal differences when it comes to outcomes. In terms of the limitations, it's funded by Basalia Pharmaceuticals, which is the manufacturer of ceftavipril. It has a lower percent of MRSA, so like 25% of the participants only have MRSA, so that's a little bit low from my point of view. And last is the daptomycin dose that they use is also on the lower limit of normal. Only 11% of the participants in the daptomycin group received doses greater than 7 mg per kg. So, our key takeaway from this presentation is that it's not yet recommended to be applied in practice. First of all, it's just recently approved last month, so I believe it's not yet available in majority of the sites. Second, it is a little bit expensive. What I found was for a 100 mg vial, it costs between $3,000 to $4,000. But for one dose, they need 500 mg, so the cost alone might be a hindrance. So, my recommendation is we don't change the standard of care practice. We still use vancomycin as our first line, daptomycin as our second line. And if that's not working, we definitely need to consult ID service to try other agents before we can use Ceftabipro. All right, these are my references. So, this brings me to my polling question. Question number one, what is your institution's first line agent for MRSA bacteremia? Is it A, daptomycin, B, linazolid, C, ceftaroline, or D, vancomycin? All right, vancomycin, perfect. Yep, that's also what we use in our institution. All right, and the second polling question. What does your institution use in adjusting vancomycin doses, A, AUC over MIC, B, TRUF, D, both AUC and MIC and TRUF, or D, neither? All right, both, yeah, perfect, yep. For the guidelines, I actually recommend AUC and MIC now, but I know a lot of institutions still use TRUF, so I assume a lot use both. All right, that is the end of my presentation. What are your questions? I was curious why you didn't think vancomycin was a part of this study, given it's a first line agent for Sepharis. Yeah, so I believe they didn't use vancomycin because there was a study 15 years ago that compared daptomycin versus standard of care treatment. So at that time, vancomycin was the standard of care. So they're just, since they've shown non-inferiority between daptomycin and vancomycin. So they just extrapolated their results. That's why they used daptomycin. They didn't mention any reason why, but I believe that could be a potential reason. Do you think any logistical concerns using vancomycin? Yeah, because I believe there are, so from a pharmacokinetic standpoint, you know, there is a differences in the levels that, or sorry, the pharmacokinetic parameters that we use. Some institutions will use TRUF, some institutions use AUC-MIC. So again, in terms of the protocol, you know, some institutions have a pharmacist-led vancomycin protocol and some institutions don't. So maybe that differences in the logistic side of things makes it hard for the trial. It's not that standardized. That's why they chose daptomycin instead. Yeah, I agree. I think it would be just much easier to use dapto. Another question was, where does this fit in with another cephalosporin agent like ceptariline now that we have this large randomized control trial data? Yeah, so that's a good question. Thank you for that. They actually, since they're the same fifth generation cephalosporins, they're active against gram-positive and gram-negative. There was a study, a head-to-head study that was conducted in the UK and Ireland that showed that ceptobiprole has a little bit better activity against MRSA, even though the ceptariline has a lower MIC breakpoint. But in all the patients in that ceptobiprole group, all of them are susceptible to MRSA, as opposed to ceptariline that had 10 out of 230 patients that are not that susceptible. They needed a little bit intermediate and high susceptibility against ceptariline for MRSA. So I believe, based from the results of this trial, ceptobiprole could be considered as a treatment option after ceptariline, since we have more data and ceptariline has been used or is being used a lot now in the institutions, even though it's not FDA-approved for bacteremia. Okay, well, thank you, RJ. That's going to conclude our portion of Q&A. And with that, I'll introduce our final presenter, Madison Koons. Thank you very much. I am Madison Koons. I am the Emergency Medicine and Critical Care P2x2 resident at Massachusetts General Hospital in Boston. And I will be presenting my journal club today on the Early and Empirical High-Dose Cryoprecipitate for Hemorrhage After Traumatic Injury, also known as the CRYOSTAT-2 Randomized Control Trial. So a brief background before I go into the trial. As we know, trauma causes a multifactorial clotting disorder that can exacerbate bleeding and can confound surgical and or resuscitation attempts at hemostasis. Patients undergoing or that undergo a significant trauma can, what routinely happens is, so fibrinogen is a protein in your blood. It's soluble and it circulates your body. But when someone experiences a trauma and is injured, the coagulation cascade is activated. Fibrinogen is transferred to fibrin, which helps stabilize platelets in place at the site of injury to help stabilize and form a clot. There in the patients that experience trauma, many of you may know as the triad of death. So I experienced profound lactic acidosis, hypothermia, as well as coagulopathy. So ultimately, a lot of times patients have lower fibrinogen levels due to consumption fibrinolysis or dilution. Many observational studies previously have showed that low fibrinogen levels in trauma patients has been associated with increased risk and mortality. There are major hemorrhage protocols that I'll reference in the study that will help divide the delivery of blood components during initial resuscitation to help deliver a balanced ratio of red blood cells, plasma, and platelets to approach concentrations equivalent to whole blood. And then patients that have low fibrinogen ultimately need concentrated fibrinogen products in order to raise levels to a normal range to support their coagulation when bleeding. In terms of whole blood that I discussed previously, patients that receive a major hemorrhage protocol ultimately receive that ratio of red blood cells, platelets, and then fresh frozen plasma. Fresh frozen plasma can be broken down into specific fibrinogen replacement therapies that I'll be talking about today. So the standard of care for the US and UK for fibrinogen replacement is cryoprecipitate and then fibrinogen concentrate. Fibrinogen concentrate is a more purified form of cryoprecipitate. Cryoprecipitate contains fibrinogen as well as other clotting factors while fibrinogen concentrate only contains fibrinogen. So some comparisons between the two. Cryoprecipitate needs to be thawed and it is typically a larger volume. Fibrinogen concentrate has to be reconstituted, ultimately usually a lower volume and it's typically more expensive. When deciding between the two agents, it's usually recommended to use what your institution has available. But if there are two agents that you have choosing between the two, it could come down to the volume size. So before CryoSTAT-2, there was the CryoSTAT pilot trial that essentially looked at feasibility. So it looked at, can we administer cryoprecipitate in a feasible amount of time? As we know that it is a product that needs to be thawed. So this study looked at two UK trauma centers and the administration of 10 units of cryo in addition to the empiric massed hemorrhagic pack, which included six units of pack red blood cells. Ultimately, the study found that this was feasible to administer with the mean time to administration being 60 minutes. They found that this cryo raised fibrinogen levels and then it did show a trend toward decreased mortality, which led to other future studies, including the PAMPER trial, which essentially looked at pre-hospital administration of plasma. So this included 27 area medical transport services, two centers in the U.S. And they were randomized to the intervention with two units of thawed plasma for standard of care. And this study ultimately included that early or pre-hospital administration of plasma actually did decrease mortality in patients at high risk or a bleeding without significant harm. And they showed like a 10% mortality, which ultimately led to our clinical question today and the Cryostat-2 trial. So the Cryostat-2 trial essentially hypothesized that early empirical high-dose cryoprecipitate in addition to a standard of massive hemorrhage protocol would improve survival in the first 28 days after hospital admission following injury. With the main clinical question of the study essentially being, should fibrinogen treatment be given empirically and in high doses to rapidly correct levels? Or should it be given later in the course of bleeding as done typically in clinical practice? This study was a multi-center phase three randomized open-label parallel group trial in 26 major trauma centers across the U.K. and U.S. from August 2017 to November 2021. It included patients that were greater than or equal to 16 years old, had evidence of active hemorrhage requiring the activation of a local massive hemorrhage protocol, indicating a systolic of less than 90 at any point, and then started or received at least one unit of any blood component. Patients were excluded if patients were transferred to another hospital, if their injuries were incompatible with life, or if it was three hours since the initial injury. Patients received or were randomized to either standard of care. So again, the local standard hemorrhage protocol or treatment, which include the standard of care plus three additional pooled units of cryoprecipitate. The primary outcome of the study was all-cause mortality at 28 days, and then secondary outcomes include all-cause mortality, including death from bleeding at 6 and 24 hours, and then at 6 and 12 months. They looked at the patient's specific transfusion requirements at 24 hours. They looked at critical care and hospital length of stay, destination at discharge, quality of life measures, and then GCS scores at discharge or at day 28 and 6 months. And then they also evaluated safety outcomes, including symptomatic venous or arterial thrombotic events up to day 28 or discharge. There was ultimately 9,036 patients screened. 1,600 were randomized. 760 included in final analysis in the cryo group, and 771 in the standard of care. The patients that were included were from 25 major UK trauma centers, and then one center in Texas in the U.S. To note, 42% of patients in the cryo group actually did not receive cryoprecipitate, and this was due to no evidence of active bleeding. Hemostasis achieved, or the patient died. Baseline characteristics between the two groups were very well-balanced, with the median age being around 39. Eighty percent of patients were male. They had similar injury severity scores of a median of 29. The injury type between the two groups was greatest as a blunt injury, and then around 24 to 29% of patients had severe head injuries. Thirty percent of the patient population did have an admission systolic blood pressure of less than 90, the median being 100 across the groups. And 43% of patients in both groups received blood component transfusions. Eighty percent received transaminic acid before arrival. So a pretty sick patient population, which was the goal of this study. In terms of results regarding the primary outcome, so if you look in the middle of the graph at the darker line, you can see that this compared the 28-day mortality of the standard of care versus the cryo group, and ultimately they found no difference in terms of mortality. They predicted a 26% mortality, and this is exactly what they found in both groups. And I will go into this further, but as you can see, the blue line shows penetrating injury. The orange line is blunt injury with some differing results. So the blue line showing that possibly having an increased mortality of patients received cryo and penetrating injury. And then in the standard of care group, if they had a blunt injury, possibly had decreased mortality if they received cryo, although that was not statistically significant, but I'll have the numbers on the next slide. In terms of secondary outcomes, there was essentially no differences in any secondary outcomes or safety outcomes. The incidence of thromboembolic events at 28 days were similar between the two groups. The medium time to death was interesting. It was 191 minutes in the cryo group versus 86 in the standard of care. Although the authors did not comment on what exactly they thought this meant or why they thought this was differing between the two groups. In the pre-specified analysis, the authors were curious of the time cryo was administered and the outcomes that that showed. So they stratified based on the time that the patient received cryo. They found that if a patient received early cryo, they had possibly increased mortality with an odds ratio of 1.45 or 1.16 if administered up to an hour. And then they noted this sweet spot in time that the patients received, if they received cryo from 61 to 90 minutes, that they actually had a reduced mortality risk. So an odds ratio of 0.57. And then if administered greater than an hour and a half, then they essentially found no benefit really. Another, the pre-specified analysis that I noted previously on that chart, but again, honing in on the point that they found a decrease in mortality or signal to mortality in patients that received cryo for a blunt type injury and then a increased mortality that was statistically significant in patients with a penetrating injury that received cryoprecipitate. There was no difference in terms of age, sex, or the type of head injury that they had as well, which is just an interesting point. And I think warrants further research in that specific area of injury type. So ultimately, the authors concluded that among patients with severe hemorrhagic bleeding, activation of a massive hemorrhoid protocol, the addition of early and empirical high-dose cryo to standard care did not improve all-cause 28-day mortality. And it may actually signal an increased mortality in patients with a penetrating injury or if cryo was administered early. This study had several strengths. So it had a patient-centered outcome of mortality benefit. It looked at, it was multi-centered, a multi-centered study. Patients had very well-balanced baseline characteristics. Patients did have a high injury severity score, thus increasing the chance of finding treatment effect. And the results are applicable to other advanced trauma centers. They also did have a minimal loss of patients to the patients for the primary analysis. Some weaknesses is that it was a trial that was primarily took place in UK hospitals with only one hospital that took place in the US. It was unblinded, leading to the risk of bias. The intervention was empiric and not tailored. There was, again, that signal to benefit in blunt trauma subgroup, but a signal to harm and penetrating trauma subgroup, which the authors could not conclude why that exactly happened. And there were crossover between groups. So 15% of patients in the cryo group did not actually receive any. And then 9% of the control group actually did get early cryo. So some main takeaways from this trial was that essentially the empiric use of cryoprecipitate in patients with severe hemorrhagic bleeding does not improve mortality. The median time to the first transfusion was greater than an hour after a while, which again just reflects the logistical challenges of preparing frozen blood components. There are high risks of giving. There is a proposed high risk of giving fibrinogen in patients that already have normal to high levels. It can cause pro-inflammatory or pro-coagulant effects, leading to thrombosis. So it's not without risk. There was increased mortality in penetrating injury and the trends in patients who receive cryoprecipitate, which again early indicate further research to fully characterize the safety of giving fibrinogen in patients who may have not developed low fibrinogen levels already. And then the question that really was unanswered in the study is, what is the benefit of giving cryoprecipitate to a protocol that doesn't already include cryoprecipitate? As we know, there was crossover seen in this trial. Okay, this brings me to my two polling questions. So polling question number one, does your institution's massive transfusion protocol contain cryoprecipitate? So it looks like the majority of institutions, massive transfusion protocol does not at 63%, but almost interesting result of 50, I think 50 or 38% does. So majority do not, which I kind of figured. And then our next polling question, which segued from this trial, but would the use of TEG change your use of cryoprecipitate? And 91% of patients said yes. And that's exactly where my head went after reading this trial. It seemed that giving empiric fibrinogen products to replete does not lead to a mortality benefit. And it seems like the further research that needs to be taken place is more patient-guided administration of these products. So I agree with the audience. These are my references. And thank you, everyone. I'm happy to answer any questions if anyone has any. And I had a couple. What do you think about, you know, in trauma literature, you see this with sepsis about timing. What do you make of this random time interval of possible benefit of early cryo in that 45 to 60-minute window, if I remember correctly? Yeah, it was the benefit being in like 61 to 90 minutes, which was very interesting. Yeah, the authors didn't quite comment on that exact timing. I mean, I think that's definitely a place where future research can occur. My thought process is possibly due to the mechanism of trauma as like the underlying pathophysiology of timing has to do with having a benefit in that like sweet spot. So I'm kind of thinking there's like an underlying physiologic process that's occurring in that time frame. Great. Well, I think we're just past the top of the hour, and I don't have any other questions from our attendings. So with that, I want to thank all of our presenters today, as well as the audience. And thank you, Madison, too, for just presenting that journal club for us. Please join us on the third Friday of the month from 2 to 3 p.m. Eastern Standard Time for the next Journal Club Spotlight on Pharmacy. This concludes our presentation today. I hope you all have a wonderful weekend.

Webcast

Pharmacology

Sepsis

Trauma

Pulmonary

Antibiotics

Hemorrhage

Journal Club Spotlight on Pharmacy webcast

critical care

trauma management

ventilator-associated pneumonia

Amikin-Hall trial

ceftobiprol

Eradicate trial

staphylococcus aureus bacteremia

Ventilator Associated Pneumonia VAP

CryoStat-2 trial

hemorrhage after traumatic injury

Professional

Select

2024