Hello, and welcome to today's Journal Club Spotlight on Pharmacy webcast, which is supported by the Society of Critical Care Medicine's CPP section. My name is Brian Lopez, clinical pharmacist lead at Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire. I'll be moderating today's webcast. A recording of this webcast will be available to registered attendees. Just 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 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 Brooke Smith, PGY-2 Critical Care Pharmacy Resident at University of Illinois at Chicago in Chicago, Illinois. She will present on Early Adjunctive Methylene Blue in Patients with Septic Shock, a Randomized Control Trial. Our second presenter is Austin Rowe, PGY-2 Critical Care Pharmacy Resident at Johnson City Medical Center in Johnson City, Tennessee. He will present Hydrocortisone in Severe Community Acquired Pneumonia. And our third presenter is Jordan Genrette, PGY-2 Emergency Medicine Pharmacy Resident at University of Colorado Hospital in Aurora, Colorado. She will present on Efficacy and Safety of Early Administration of Four-Factor Prochrombin Complex Concentrate in Patients with Trauma at Risk of Massive Transfusion, the ProCOAG Randomized Clinical Trial. And now I'll turn things over to our first presenter. Hi, everybody. My name is Brooke. I'm going to be presenting on a study by Ibarra Estrada and colleagues out of Mexico called Early Adjunctive Methylene Blue in Patients with Septic Shock, a Randomized Control Trial. All righty. So to move on with our background. So current indications for methylene blue include isophosphamide toxicity, vasoplasia from CT surgery, methemogloanemia, and then lastly, shock secondary to beta blocker and calcium channel overdose. So as you notice, septic shock is not currently one of the common indications for methylene blue. Looking at methylene blue overall. So for its mechanism of action, it inhibits inducible nitric oxide synthase, leading to inhibition of guanylate cyclase. Through doing this, it decreases levels of CGMP, and through that, it decreases vasodilatory effects. Through these mechanisms, it causes an increase in systemic vascular resistance, which you know is one of the underlying etiologies of distributive shock. For adverse events, so it is a MAOI, so it does have a black box warning for serotonin syndrome. It also causes blue discoloration of the skin and urine. Some other less severe side effects include flushing, dizziness, chest and limb pain. And then we're going to discuss this a little bit more later on, but it has been found to have a worsening arterial oxygenation and P to F ratio. Methylene blue can lead to pulmonary vasodilation and also decreased gas exchange across alveoli. So therefore, before this study, there was some concern about using it in patients with ARDS. Looking at the cost of this medication, so we'll go through the dosing more later on, but just know that looking at the average wholesale price of methylene blue for this study, it would have cost about $1,800. So prior to the study, there were two other studies that have been performed. So the first one is Kurov and colleagues. This was a randomized controlled trial looking at methylene blue and they dosed it as two milligrams per kilo as a bolus. They slowly titrated up and continued it as a continuous infusion versus placebo. This was looking at patients with a newly diagnosed septic shock and it included 20 patients. They found that this study in methylene blue reduced adrenergic support and infusion of methylene blue did not have any serious adverse events on any sort of end organ dysfunction. Memes and colleagues in 2002 published another randomized controlled trial, slightly different dose at 0.5 milligrams per kilo per hour for six hours versus placebo. This was also looking at patients with severe sepsis, included about 30 patients, and they found no difference in mortality rates. They found that methylene blue did not affect cytokine levels. However, there was a transient increase in arterial pressure. So this brings us to our study's purpose today is to assess whether adjunctive methylene blue can reduce time to vasopressor discontinuation in patients with septic shock. Looking at the study design, so this was a double-blinded randomized controlled trial. This was done at a single center at an academic medical center in Mexico and it was a placebo controlled trial. So a little bit different from the doses that we looked at earlier in the previous studies. So this looked at methylene blue at 100 milligrams and 500 milliliters of normal saline infused over six hours once a day for three days. The other studies, as you remember, just did a continuous infusion. And then again, this was placebo controlled. So their inclusion criteria was pretty broad. So their inclusion criteria was pretty broad. Adults who met the sepsis 3 definition, they ended up including 91 patients. And then looking at their exclusion criteria. So as you can see here, majority of patients were excluded for COVID. Due to the IRB process in Mexico, they did have to exclude patients with COVID just since their underlying etiology was unknown at the time. And so this accounted for roughly half of their exclusions. So other notable exclusion criterias include greater than 24 hours since initiation of norepinephrine, major burn injury, any sort of patient with a pending source control surgery, any other forms of shock. So excluding some of those mixed pictures. Anybody who was acutely enough to have a high probability of death within 48 hours. And then due to the black box warning, they did exclude patients who had a recent use of SSRIs. Their primary outcome was time to vasopressor discontinuation at 28 days. Some other notable outcomes included a vasopressor-free days at 28 days, days on mechanical ventilation, 28-day mortality, ICU and hospital length of stay, and then also adverse events. Looking at their statistical tests, for normally distributed data, they used means and standard deviation, while with any skewed data, they used medians and interquartile ranges. For any sort of continuous variables, they used a student's t-test or a Mann-Witt AU test. When comparing variables at different points in time, they used repeated measures analysis and variance or Friedman's test. For p-values, anywhere less than 0.05 was considered statistically significant. And then they required 88 patients to provide a statistical power of 88%. So it was an adequately powered study for their primary outcome. Moving on to results. So looking at the patient population, as we can see here, a fairly younger patient population at least, a little bit different than what we see in Chicago, average age of around 40%. They had a pretty quick time to enrollment. So from shock diagnosis to intervention, it was about eight hours. When looking at positive fluid response at enrollment, it was about 50%. Their norepinephrine dose at baseline was around 0.4 mics per kilo per minute. And then about 80% of patients were on vasopressin. Nearly all of the patients were mechanically ventilated and they had an average median SOFA score of 10. Of note also, as we mentioned earlier, there was a concern in our ARDS patient population due to the potential worsening of P to F ratio. And about half of the patients in this study actually were diagnosed with ARDS. When looking at our efficacy outcomes, so first time to vasopressor discontinuation at 28 hours, we can see that this was statistically significant with methylene blue having 69 hours versus placebo at 94 hours. Unsurprisingly, with patients getting off of vasopressors quicker, they had more vasopressor-free days in the methylene blue arm and as well, they were able to get out of the ICU much quicker. With getting out of the ICU quicker, as we know, they had a shorter hospital length of stay. So really overall, methylene blue seemed to decrease time on vasopressors, get patients out of the ICU quicker and get them home quicker as well. There was no difference in 28-day mortality though. When looking at adverse events, so the most common adverse event seen with methylene blue was green to blue discoloration of urine. This occurred in 93% of the patients. So almost all patients who received methylene blue had this. They also did look at maximum methemoglobin saturation and this was higher in patients with the methylene blue group compared to patients with placebo. With that being said though, it didn't necessarily change anything in terms of end organ damage. So there was no difference in ejection fraction, P to F ratio, CM Kretnin or liver function tests. Moving on to the authors conclusions. So the authors did talk about some of their limitations. They said this was a single center study and they did say that patients at this specific institution seemed to be discharged quicker than some of the other institutions. Most of the patients were diagnosed in a non-ICU at the time, whether this was a general ward or an emergency department. So maybe their outcomes would have been even better if the patients were diagnosed in the ICU where there's just more resources and more hands on deck. The surviving sepsis campaign was updated during their enrollment criteria. However, almost all patients did receive corticosteroids in the study. So it sounded like they were still following the study or still following surviving sepsis campaigns when they were updated. We talked a little bit earlier about the COVID-19 pandemic that slowed enrollment. It was underpowered for mortality. And then the authors did know that it was not completely blinded due to the blue urine. So overall, they concluded that early adjunctive methylene blue administration reduced vasopressor duration, cumulative fluid balance, and ICU and hospital length of stay. There were no severe adverse events related to its use. Moving on to what I thought when I read this study. So I think it was a great study in the fact that it evaluated hard outcomes. So it truly looked at how long they were in the ICU, how long were they on vasopressors, 28 days mortalities. I think the authors did a great job with this. They did include ARDS patients. And I think this was almost maybe a nice myth buster for the previous studies that showed a concern in ARDS patients. However, there is a lack of true blinding. And I'm not really sure logistically how authors could have combated this just due to the blue discoloration of patient's urine. It was single center. And then interestingly enough, they did exclude epinephrine, phenylephrine, and angiotensin II in this study. So really patients got their norepinephrine and then they got vasopressin, but they didn't evaluate patients who were on three to four to five vasopressors. So it would be interesting going forward to see if methylene blue still had any sort of efficacy with this more severe shock, or if it should truly be more of almost where corticosteroids are right now in the guidelines where when you're adding on that second presser, that's when methylene blue should be added on. So overall, I concluded that this is the most robust study to date evaluating the safety and utility of methylene blue in shock. Methylene blue could potentially decrease time on vasopressors and ICU length of stay. It appeared to be well tolerated with minimal risk. However, there are some potential for logistical issues. I think all of us on this call are burdened and annoyed by all of the ongoing shortages that we're having to deal with and looking at the other indications for methylene blue, such as isophosphamide toxicity, and methemoglobinemia. If this medication went on shortage because everybody was using it for shock, that could really tie our hands up with other indications where maybe there's more robust literature for it. Overall, I think this is a really thought-provoking study, but personally I would want to see more studies potentially multicenter and with the new updated surviving sepsis campaign guidelines to see if this is a viable option going forward. Now moving into our first audience question. So do you use methylene blue for septic shock at your institution? Yes, we routinely use methylene blue, not routinely only in specific clinical scenarios. And then finally, no, I've never used methylene blue for septic shock. And it looks like about 58% of participants chose B, so not routinely used, but really only in specific clinical scenarios. I would say at my institution, we have never, at least in my experience in the last year here, used methylene blue for our septic shock patients, really just the other indications that we spoke about earlier. And then our last audience question, based on the trial presented today, along with previous studies, will you start recommending methylene blue for the treatment of septic shock? So A, yes, I will begin recommending methylene blue on patients, B, I would not oppose if other providers wanted to start using it, or C, further studies are warranted before recommending. And it looks like it's almost an even split. Maybe a little bit more votes towards further studies are warranted, but about 40% of participants would be okay using it if their provider wanted it. All righty, and those are all of my slides for today, so thank you so much for letting me speak about this, and I'll take any questions now. Great. So, the first question that we have is, how would you differ between surviving sepsis campaign bundle compliance versus effects of methylene blue? That's a great question. I mean, I think that's honestly why we need more multi-center studies, because I don't think every hospital is always compliant with the bundle, and I think we need more real-world data implementing methylene blue at various sites, but I don't really think there would be a great way to control for making sure people are doing their appropriate sepsis bundle. Great. The second question is, are there any patients you wouldn't want to use it in? What's the actual risk of serotonin syndrome if the patient is on an SSRI, for example? Yeah, that's a great question. I'm not sure of the exact incidence of serotonin syndrome for patients with SSRIs and methylene blue. As we know, that was an exclusion criteria in this study, so I think if I were to use methylene blue in a septic patient, I would follow the exclusion criteria of this study. With the exception of potentially COVID, I would be more likely to bypass that exclusion criteria, but definitely anybody who is on an SSRI, I would hold off on giving methylene blue. Great. That concludes our Q&A session for Brooke. Thank you, Brooke. 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. If you could please just answer, how many attendings are you viewing this webinar with? Great, thank you. And now I'd like to introduce our 2nd presenter, Austin Rowe. Thanks, as said, my name is Austin Rowe, and this is hydrocortisone and severe community acquired pneumonia, also known as the Cape Cod trial. This was published in the New England Journal of Medicine, March 21st, 2023. So, I have nothing to disclose. For a background, next, community acquired pneumonia, or CAP, remains a major cause of morbidity and mortality. It's actually the 9th leading cause of death in 2019. Pneumonia also leads to pulmonary and systemic inflammation, and so the anti-inflammatory effects of glucocorticoids may be able to help mitigate some of these inflammatory consequences. Looking at previous literature, which there's been a decent amount of, there's been 7 randomized control trials, or RCTs, that have demonstrated glucocorticoids have various positive effects. Of note, only 1 of them actually demonstrated a mortality benefit. And there's been 2 meta-analyses that have actually shown conflicting results. The first one, which included only high-quality, low-risk-of-bias data, found that there was no difference in mortality, while another meta-analysis that included other studies that had a higher risk of bias, that one found that there was a difference in mortality, and it reduced mortality. And so, with the data being conflicted, this trial was performed to try to find out the difference in mortality. So, the purpose, evaluate the effect of early hydrocortisone treatment on 28-day mortality in patients admitted to an intensive care unit for severe community-acquired pneumonia. Onto our methods. It was a multi-center, double-blind, randomized control superiority trial that was conducted in 31 French centers between October 28, 2015 through March 11, 2020. So, for the inclusion criteria, the patients were included if they were at least 18 years of age, diagnosed with severe CAP, and for their definition of severe, that was initiation of mechanical ventilation with a positive end-expiratory pressure, or PEEP, of at least 5 centimeters of water, a high-flow nasal cannula or non-rebreather with a P-to-F ratio of less than 300, or a pneumonia severity index greater than 130, which is also group 5 on the pneumonia severity index. And just as a brief refresher, what that is, it's a scoring system that can be used to help determine the level of care that a patient needs when they're diagnosed with pneumonia, whether they need to be hospitalized or treated outpatient. It also is correlated with mortality, and a score of 130 correlates to about 8 to 9 percent mortality. The exclusion criteria, patients were excluded if they had a do-not-intubate order, they were diagnosed with influenza, and that's given the fact that it's kind of controversial for influenza, but may actually cause harm, and then septic shock because they can actually have benefit with septic shock, and then if there's any other indication for corticosteroids, they were also excluded. So patients were randomized one-to-one to either receive hydrocortisone or placebo. Hydrocortisone was dosed as 200 milligrams per day as a continuous infusion for 4 days, and then on day 4, the patients were either going to get an 8-day taper or a 14-day taper. Essentially, if the patient condition improved, they would taper off within 8 days or at ICU discharge, and if condition did not improve, they would taper off within 14 days or at ICU discharge. And to determine whether a patient was a candidate for 8 or 14 days, the criteria for that was they would get 8 days if the P to F ratio was greater than 200, if the SOFA score was reduced from their baseline score, or if they had a high probability that the patient would be discharged from the ICU by day 14, as estimated by the treating clinician. To give you a visual representation of what these different day tapers look like, at the top here, we have this 14-day taper, where essentially at day 4, they would be determined to either have 8 or 14 days, and then they would be tapered off in the fashion you see there, expressed as milligrams per day. And then the 8-day taper would begin to taper right on day 4, reducing to 100 milligrams for 2 days, and then 50 milligrams for 2 days. And then again, just as a reminder, if they were discharged from the ICU, the regimen would be cut off right when they're discharged from the ICU. So looking at our outcomes, the primary outcome is all-cause 28-day mortality. Secondary outcomes include all-cause 90-day mortality, as well as ICU length of stay, endotracheal intubation, and vasopressor initiation. Safety outcomes include secondary infections and gastrointestinal bleeding and insulin usage by day 7. It was estimated that the trial would need about 1,200 patients to meet 80% power to detect a 25% reduction in mortality by day 28. There were also two planned interim analyses. And of note, the COVID-19 outbreak actually paused this trial. And during that second interim analysis, after the outbreak had already begun, they decided to end the trial early, given the ongoing pandemic. On to the results. The trial enrolled 795 patients, so it did not meet the power for enrollment. The median age was about 67 in both groups. COPD was in 22% in the hydrocortisone group and 27% in the placebo group. And looking at diabetes, that's 24% in the hydrocortisone group and 22% in the placebo group, which, at least looking at our patient population, where I'm from, that's pretty low, considering the patients that typically get admitted to our ICUs for pneumonia. And looking at mechanical ventilation at baseline, that was in 45% in the hydrocortisone group and 44% in the placebo group. And then the breakdown between invasive mechanical ventilation and the non-invasive mechanical ventilation, like BiPAP, was kind of 50-50 between that 45%. The median pneumonia severity index was 127 in the hydrocortisone group and 130 in the placebo group. And then, interestingly, the C-reactive protein was 26 in the hydrocortisone group and 24 in the placebo group. I'll talk a little bit more about the C-reactive protein later, but just keep that in mind. Looking at the pathogens that were identified in this trial is also pretty interesting. So 47% in the hydrocortisone group had no pathogen identified, while it's 43% in the placebo group. And then those that had at least one pathogen identified was 53% in the hydrocortisone group and 58% in the placebo group. And the most common pathogen, by a pretty large margin, was Streptococcus pneumoniae. And then the next most common was Legionella, followed by Staph aureus and H flu. So on to the medications administered. So third-generation cephalosporins were administered in 78% in the hydrocortisone group and 80% in the placebo group. And then macrolides, we see 72% hydrocortisone and 75% placebo, which makes a lot of sense considering what we see here. That's typically what we see. Fluoroquinolones were used, but pretty rarely, 16% in the hydrocortisone group and 17% in the placebo group. And then of note, the hydrocortisone duration was only continued for five days as a median in the hydrocortisone group. The placebo was continued for six days in the placebo group. On to our mortality outcomes now. 28-day mortality occurred in 6.2% in the hydrocortisone group, 11.9% in the placebo group. That percent difference was negative 5.6, being statistically significant, favoring hydrocortisone. 20-day mortality was also significantly lower in the hydrocortisone group as well, with a percent difference of negative 5.4%. And looking at the subgroup analyses, I think this is kind of interesting to see who had the greatest benefit looking at these subgroups. And this is for the 28-day mortality and the primary outcome. And I really just want to bring your attention to the CRP. Those that had greater than 15 on the CRP had the greatest benefit in mortality, the biggest reduction, which is kind of interesting when we go forward thinking about the trials that came out for COVID. We found that those that had COVID-19 pneumonia tended to do much better with our steroid treatments and with some of our immunosuppressive treatments like paracetamib and tocilizumab with elevated CRPs. I think that kind of is a theme here going on with a lot of these pneumonia. So looking at our secondary outcomes now, the intubation when not intubated at baseline occurred in 19.5% in hydrocortisone and then 27.7% in placebo, which the hazard ratio did not cross over one, so that was considered statistically significant. Vasopressor initiation when not receiving vasopressors at baseline was also lower in the hydrocortisone group, 15.3% compared to 25% in the placebo group, and the hazard ratio did not cross over one either. On to the safety outcomes. Those that had newly acquired hospital-acquired infections occurred in 9.8% in the hydrocortisone group, 11.1% in placebo, and that was not statistically significant. GI bleeding was also pretty low in the hydrocortisone group, and it was even slightly higher in the placebo group, but that did not reach statistical significance. Looking at our safety outcomes, we can see that the patients administered any insulin at all was higher in the hydrocortisone group, 58% compared to 45% in the placebo group. And then when we actually look at how many units were used each day by day seven, we can see that hydrocortisone was higher, and that was statistically significant, which makes sense given the side effects of hydrocortisone. On to the discussion. This was one of the largest trials evaluating corticosteroids for severe CAP. It had pretty balanced baseline characteristics, and it rapidly enrolled its patients and had a very rapid time to the first study drug administration so that we can try to mitigate those anti-inflammatory effects and see what that benefit is. On to the limitations. The observed mortality was lower in the control group than was anticipated. The trial also ended early and did not meet power, unfortunately, due to the COVID-19 pandemic. And so based on the timing of when this trial was going on, it actually, enrollment continued until March 11, 2020. And if you think back a few years ago now, that's when the pandemic was kind of reaching its new heights and when it was officially declared to be a pandemic. But we know that there was probably lots of unrecognized COVID patients even before March, even as early as perhaps December 2019. So it's kind of unclear how many of these patients might have had COVID-19 that were enrolled in this trial. We do know based off of some literature that came out later that steroids tend to help in these patients a lot, particularly dexamethasone, but there's also some data saying that hydrocortisone helps in COVID-19 as well. So it's unclear if that had any sort of skewing of the results in this trial. My conclusions and takeaway, early cortisone therapy can reduce 28-day mortality in patients admitted to the ICU for a severe cap. I think obtaining a CRP might be able to help us find patients that can have the most benefit, given that subgroup analysis with the CRP greater than 15 having the greatest outcomes and even thinking towards later studies for COVID-19 where we know that patients that have pneumonia and high inflammatory markers, maybe they can benefit from some steroids. These results don't necessarily apply to patients with uncontrolled diabetes based off of the low incidence of diabetes and the baseline characteristics and relatively low daily insulin usage compared to some patients that we have here, at least where I'm from. And then a tapered regimen is not needed based on the short treatment duration. Most of these patients were discontinued at day five, even before the taper was truly started. So that's not needed. For the first audience polling question, do you regularly use flucocorticoids for CAP in your practice? Yes or no. No. Yeah, that's my experience as well. 94% no, 6% yes. And for the next audience polling question, will this article change your current practice? So still mostly no, a little bit of yeses. I think this one's definitely controversial so that's kind of something I was expecting. I'd almost see it closer to 50-50. But I think this is this is very interesting and I think that I would love to see some more articles looking at those specifically with high inflammatory markers and seeing how that does. I think that would be a more interesting trial to come out in the future as well. So I think this is a this question is not over yet. But thank you all for for listening and I would love to answer any questions you may have. Thank you Austin. So the first question we have is how do you think the study outcomes would have been different with IV bolus hydrocortisone dosing compared to continuous infusion? Yeah that's that's a good question. I personally don't think it would be very different. I do know that some previous literature has shown that the IV bolus dosing and the continuous infusion probably there is no difference. I do know that given the shortage right now we've actually in my institution we switched to continuous infusion. We used to do the bolus only. We did that to try to preserve our supply and not have any vial wastage. But to answer the question I don't think that would affect the results. I think either way would be fine if that's what you would prefer to do. The second question is do you have any thoughts on how the results might have differed had they used something like methylprednisolone or dexamethasone as opposed to hydrocortisone? So that is a really interesting question that I don't have an answer to. Thinking about it I do know that hydrocortisone that's a really good question. Hydrocortisone definitely would be nice in those patients that develop into septic shock and that was an exclusion criteria here. But I don't have a good answer for that. I do know again dexamethasone for COVID-19 was the one that they studied and the one that had the most benefit. But I don't have a good answer for you to be honest. And then final question is what was the proportion of moderate to severe ARDS in each group? And given the inclusion criteria was it really a trial of corticosteroids in early ARDS? Yeah I think most of these patients were pretty close to that moderate or more ARDS. So definitely could be making the argument there that this is looking at patients with ARDS. I think based off of their different definition of severe community-acquired pneumonia I think a lot of patients are also going to be have ARDS at the same time. And we do know that dexamethasone based off the dexARDS trial has potentially some benefit in ARDS. And so this is kind of just more evidence that's saying the patients that have really severe pulmonary problems like whether it be pneumonia, ARDS, corticosteroids probably help with that. Great, thank you. That concludes our Q&A session. Now I'd like to introduce our final presenter, Jordan. Great, thank you. Yes, I'm Jordan. I am the University of Colorado Emergency Medicine resident this year and today we are going to be talking about the efficacy and safety of early administration of four-factor prothrombin complex concentrate, which I will be referring to as four-factor PCC. And this was the pro-COAG trial that was published in JAMA earlier in March of this year. So to give some background, we know that our trauma patients suffer from or are at risk from suffering from trauma-induced coagulopathy, which is the abnormal coagulation capacity attributable to that very specific trauma. We know that this is a spectrum of hypo-coagulation to hyper-coagulation depending on what time frame they are out from their initial injury. One-third to one-quarter of hemorrhaging trauma patients do experience trauma-induced coagulopathy and this is a very variable presentation between trauma patients. Early trauma-induced coagulopathy tends to occur within six hours of injury and tends to be more about hypo-coagulability. And late trauma-induced coagulopathy tends to occur about 24 hours after injury and really reflects more hyper-coagulability. That being said, patients can progress from early to late trauma-induced coagulopathy in minutes, hours, or days. It's very dependent on the patient themselves and so this makes it challenging to have a very standardized tried-and-true method of resuscitating our trauma patients. So our first polling question for this presentation is, what type of massive transfusion resuscitation protocol does your institution utilize? Is it a ratio of one-to-one, a ratio of two-to-one, or is it TEG or a viscoelastic based? So I see about 48% of responses are for A, for ratio one to one, and that's definitely reflective of what our institution does as well. But definitely interesting to see everyone's responses across the country. So four-factor PCC has been evaluated in the past for trauma resuscitation in two different retrospective trials. These were published in 2018 and 2019. These both are retrospective trials that looked at adult trauma patients that excluded patients who are on anticoagulants or had chronic liver disease. Both studies looked at the use of four-factor PCC in addition to fresh frozen plasma in comparison to just fresh frozen plasma alone. And what these studies found is that the use of four-factor PCC in adult trauma resuscitation had a shorter time to correction of INR and a faster rate of INR correction. This second study also found that there was a lower requirement for pactor blood cells and plasma transfusion in the group that did receive four-factor PCC. So the second polling question is how does your institution use four-factor PCC during trauma resuscitation? Is it a standard early administration during massive transfusion? Is it specifically for anticoagulation reversal or do we let TEG or Rotem guide our use? Okay I'm seeing primarily that by and far anticoagulation reversal tends to be the primary use for four-factor PCC and I would say that's pretty reflective of what I'm used to as well at our hospital. So that brings us to the PROCOAG trial that we'll be talking about for the rest of this presentation. This study was published in March and the researchers here hypothesized that systematic four-factor PCC combined with ratio-based transfusion would be superior to ratio-based transfusion alone in specifically reducing 24-hour blood product consumption in trauma patients. The way the study was designed, it was a superiority randomized placebo-controlled clinical trial at 12 different level one trauma centers. Patients had to be directly admitted from the scene of their injury and they could either be at risk of meeting massive transfusion or they could require massive transfusion on arrival. So their definition of at risk of meeting massive transfusion was requiring one or more unit of packed red blood cells during either pre-hospital care or within one hour of admission. The other definition of requiring massive transfusion was requiring at least three red blood cells during the first hour or more than 10 within 24 hours. So there's a pretty variable definition that patients could meet to be included in this study. For this study, patients all underwent restricted fluid expansion, so they couldn't have a substantial amount of crystalloids during their trauma resuscitation. All patients received a resuscitation ratio of red blood cells to FFP of one to one, up to two to one. All patients here as well received tranexamic acid, one gram as a bolus over 10 minutes within three hours of their injury. And this was followed by one gram IV over eight hours afterwards. Group one received four factor PCC at a dose of 25 units per kilogram and group two was placebo controlled. And both groups had to receive their intervention within one hour of presentation to the hospital. While this was a ratio-based resuscitation, patients could receive fibrinogen concentrate if their level was less than 1.5 or they could receive platelets to maintain a platelets level of greater than 50,000. For their outcomes, for their primary outcome, they looked at total number of all blood product units that were given within the first 24 hours after the patient arrived to the hospital. So this included red blood cells, fresh frozen plasma and platelets. For their secondary outcomes, they looked at individual blood components consumed within the first 24 hours. So that included like the breakdown of red blood cells, fresh frozen plasma and platelets individually. They also looked at time to hemorrhage control, 24 hour and 28 day mortality, ICU free days, ventilator free days and hospitalization status. For their safety outcomes, they really narrowed in on looking at arterial and venous thromboembolic events between those who were given four factor PCC and those who were given placebo. For their analysis, they included, they did an intention to treat analysis for all of their outcomes where all patients who were randomly assigned to treatment, including those who died within the first 24 hours, were included in their outcome analyses. Safety analysis was also performed on an intention to treat basis. They calculated that they would require 162 patients in each group for about 80% power. And they deem statistical significance to be a P-value of less than 0.05. Looking at their demographics and baseline characteristics, they ended up including 324 patients in their analyses. The average age was about 39 years old. And the only statistically different result between the two groups was that the four factor PCC group actually had less patients received tranexamic acid compared to the placebo group. So the four factor PCC group received, 76% received tranexamic acid. And that's compared to 86% in the placebo group. I do want to point out the last few lines on this table with looking at the transfusion requirements for the patients who were included in this study and very specifically the last line, where the number of those who required massive transfusion as opposed to those who were just at risk for massive transfusion was about 50% of the patient population, maybe a little bit less. So a slight majority of the patient population in this study actually were more at risk for needing massive transfusion as opposed to actually requiring massive transfusion. Now moving into the primary and secondary outcomes. For their primary outcome, they looked at the number of total blood products that were required in the first 24 hours for patients. So the four factor PCC group had 12 units on average that patients required in the first 24 hours. And that's compared to 11 units in the placebo group. This was found to have an absolute difference of about 0.2 and the result was not found to be statistically significant. They zeroed in on the subgroup of patients who required massive transfusion. And they found that, again, there was no difference in the number of blood product requirements in the first 24 hours for those who actively required massive transfusion. When they broke down the individual blood products that each patient required, they again found that there was no difference in the amount of red blood cells, the amount of fresh frozen plasma, or the amount of platelets that the four factor PCC group required compared to the placebo groups. There wasn't one product that maybe we could conserve more resources with using four factor PCC. For their secondary outcomes, they looked at mortality at various time points. And at 24 hours, 11% of the four factor PCC group had died and 13% of the placebo group had died. And this was found to not be statistically significant. These results were consistent with the 28 day mortality outcome where 17% of the four factor PCC group had died. And that was compared to 21% in the placebo group, which was again not found to be statistically significant. For their additional secondary and some safety outcomes, they looked at time to achieve hemostasis, which was 300 minutes in the four factor PCC group. And that was compared to 288 minutes in the placebo group, which again not found to be statistically significant. For hospital free days, 6.5 days was the average amount of days in the four factor PCC group. And this again was compared to seven days in the placebo group and not found to be different. Ventilator free days for each group was about four days and not found to be statistically significant. But the safety outcomes is really where we start seeing the difference between the group who got four factor PCC and the control group. So with any thromboembolic event, 35% of the four factor PCC group had any sort of thromboembolic occurrence. And this was compared to 24% in the placebo group. And that was found to be statistically significant with a calculated number needed to harm of about nine patients. And so what these authors concluded is that when compared to placebo, there is no benefit of adding four factor PCC to a ratio-based transfusion strategy in patients who are at risk of requiring massive transfusion. And as we know, there is no study without limitations or critiques that we can apply. And so this study definitely has some that are worth noting. For limitations of this study, it's important to note that less than 50% of patients required massive transfusion. And so while this was a more severe patient population than previous retrospective studies, it was not necessarily every patient requiring a profound amount of blood products. There also was no viscoelastic testing that was required to determine baseline coagulopathy in what we know is a very variable patient population. So we know these patients are at risk of hypocoagulability and then at an unspecified time point, they may become more susceptible to hypercoagulability, which does put them at a higher risk for receiving four factor PCC. They did use a ratio-based resuscitation strategy, but they also included some specialized components, including standard TXA. Patients could receive fibrinogen and they also could receive platelets based on specific lab values. And lastly, this was a surrogate outcome as their primary outcome, where the number of blood products that someone requires is important in that it does reflect their risk of end organ damage. It is a resource that we care about conserving, especially in the last year with a lot of blood product shortages, but it's not necessarily a hard outcome of the number of patients who died at a certain time point. We do know, however, that this is a relevant topic for critical care pharmacists. A lot of people on this call do take care of hemorrhaging patients either on a daily basis or on a very routine basis. This is the first randomized control trial to evaluate routine early four factor PCC administration in a trauma resuscitation protocol. So this is the highest level of evidence that we have at this time looking at early four factor PCC use. They did find no difference in blood product requirements, mortality, or time to achieve hemostasis. And so this is different than our retrospective studies and kind of provides another perspective on maybe how the safety outcomes should really be highly considered given the delayed risk of hypercoagulability in this patient population. And so with that, the main takeaway point with this study is that the routine use of four factor PCC does not improve blood product consumption requirements in patients who are either at risk of needing or actively requiring massive transfusion. And it may actually be associated with harm in a variable coagulopathic population. And with that, that is the most recent literature on four factor prothrombin complex concentrate use in our trauma resuscitation trial. In our trauma patient population, and I'm happy to take any questions that you all have at this time. Thank you, Jordan. First question is, was whole blood used at all and what effects would you expect this to have on outcomes? That's a great question. I do not believe whole blood was used in this study with the exception of pre, I don't know if I can speak for pre-hospital whole blood use, but the outcomes that they looked at for this study really looked at once the patient arrived to the hospital and they didn't report out whole blood consumption use. I would anticipate that there wouldn't be a difference between the four factor PCC group and placebo group if they looked at whole blood product requirements, because there was no difference in breakdown of like any of the individual components. And so I don't think that whole blood would be necessarily any different, would be what I would anticipate. Great. How would you say that we apply these results here in the U.S. where maybe TXA use isn't as prevalent as it was in the study? Yeah, I think that's a great question. This study enrolled patients between, I believe, 2017 and 2021. And so that was before CRASH-3 came out and kind of before the use of TXA declined pretty rapidly in trauma resuscitation. And so I think that we know that patients who get TXA late don't have as good of outcomes as those who get it earlier and really may not have that much of a benefit at all. And so I don't think the use of TXA necessarily skewed these results, but I do think it is worth noting that we don't resuscitate patients the same way that this study necessarily did in their protocol, if that makes sense. I think it is worth redoing this. You're worth kind of taking note that TXA probably didn't contribute any benefit to the outcomes. Great. And then the last question is, do you think that a TED-guided approach would yield different results? That's another great question. I think it's an interesting point because I think that, I honestly think it might provide different results where it may be able to provide a more personalized administration of four-factor PCC and really narrow in on those who are at risk for truly hemorrhaging early after their trauma. It would also prevent us from giving four-factor PCC to those who maybe are already in that hypercoagulable state. But I think something with TED-based resuscitation and probably a reason that we don't really use it as widely across the country as maybe theoretically would make sense is that it just takes a longer time to get those results back. And in someone who's truly hemorrhaging, a lot of times we don't really have a lot of time to wait for that lab turnaround. So it's an interesting concept, but I'm just not sure if it'll make it past the theoretical advantage part. Great, thank you. So that concludes the Q&A session. Thank you, Jordan. Thank you to our presenters today and the audience for attending. Please join us for the next Journal Club Spotlight on Pharmacy on May 19th from 2 to 3 p.m. Eastern Standard Time. And that concludes our presentation today.

methylene blue

septic shock

vasopressors

ICU length of stay

mortality rates

hydrocortisone

community-acquired pneumonia

28-day mortality rates

prothrombin complex concentrate