Good morning, everybody. I am so excited to be here to welcome you all to the 2021 Year in Review for the Clinical Pharmacy and Pharmacology section. My name is Erin Barreto and I'm an Associate Professor of Medicine and Pharmacy at Mayo Clinic. And I am the current chair for a few more days of the CPP section. And I will be moderating this session today. I have no relevant financial relationships and just a few house cleaning things before I have the pleasure of introducing your excellent speaker panel. As this is a flipped classroom session, you should have had access to the articles that we'll be talking about. We really hope that today is gonna be a very interactive session. The objective is to engage all of us in trying to understand these articles and their fit in practice together. So please, even if you haven't read them, do take an opportunity to skim the abstracts and listen in to what our speakers have to say. And then please enter questions in the audience response system throughout. The speakers will also have polling questions in their talks, and they'll be walking through how you can respond to those polling questions. But it's a really interactive and wonderful way for us to get a sense as the talks are going about how you are experiencing these issues in your practice. So please have your cell phone ready because we'll just have you texting and pulling up the answers there. And then lastly, feel free to use that chat function as I mentioned for those audience response questions. As I alluded to, we have three fantastic speakers today and I'm really excited to introduce them. This is our order that we're gonna go in. The first speaker that we'll get started with is Dr. Casey May. Dr. May is a Neurocritical Care Specialty Pharmacist at the Ohio State University Wexner Medical Center. She's been practicing the area of neurocritical care for six years. Dr. May has a Bachelor of Science in Biology from the University of Virginia and her Doctorate of Pharmacy from UK College of Pharmacy. After pharmacy school, she completed a PGO-1 and PGO-2 pharmacy practice residency at the University of Kentucky Health Care. And her research interests include individualization of pharmacotherapy for the neurologically injured patient, augmented renal clearance and the use of antiplatelets or the complications associated with them in subarachnoid hemorrhage and neuroendovascular procedures. Our second speaker today is gonna be Dr. Jackie Johnston. Dr. Johnston is a Clinical Assistant Professor at the Ernest Mario School of Pharmacy at Rutgers and a Clinical Critical Care Pharmacist. Her practice site is a combined surgical trauma and neurointensive care unit at St. Joseph's University Medical Center in Patterson, New Jersey, where she serves as faculty to the Surgical Critical Care Fellowship as the PGO-1 Pharmacy Resident Program Director. She received her Doctor of Pharmacy degree from the University of Connecticut and completed her PGO-1 and PGO-2 residencies at Yale New Haven. Dr. Johnston is a board certified pharmacotherapy specialist with interests in status epilepticus, infectious diseases and alcohol withdrawal. And our third speaker today is Dr. Brittany Bissell. Dr. Bissell is an Assistant Professor at the University of Kentucky in the College of Medicine, Department of Pulmonary Critical Care and Sleep with a dual appointment in the College of Pharmacy Practice and Science. Dr. Bissell received her Doctor of Pharmacy from Midwestern University followed by completion of PGO-1 Pharmacy Practice Residency at UF Health Jacksonville and a specialty residency in critical care at Jackson Memorial Hospital in Miami. She received her PhD in Clinical and Translational Sciences from the University of Kentucky in 2019 and practices as a critical care pharmacist within the Pulmonary Intensive Care Unit. Her research area of interest includes immunomodulation, endocrinology and de-resuscitation and she's active in the CPP section, the Item Writing Committee and is the incoming Vice Chair for the Scientific Review Committee. So please welcome our speakers today. We're gonna get started with Dr. May. Thank you. Thank you, Dr. Brenner for that introduction. My name is Casey and I'm gonna get started with the updates in neurocritical care. Progress the slides. Here we go. All right, so today we're going to discuss the findings of two separate articles, and we're going to jump right into the first, which is the Factor-Tenet-Inhibitor-Related Intracranial Hemorrhage article published in Circulation in 2020. I'll refer to this trial as the FICS-ICH trial as we move forward. Since their approval, oral factor-tenet inhibitors have been a major headache, pun intended, for those of us treating patients with life-threatening bleeding, including intracranial hemorrhage, or ICH. In 2016, the Neurocritical Care Guidelines published the treatment for antithrombotic-associated ICH and recommended the administration of prothrombin-complex concentrates, or PCCs, for oral factor-tenet inhibitor-associated ICH based on the available evidence in healthy subjects. As we all know, in 2018, FDA approved indexinet-alpha, a target-specific antidote for oral factor-tenet inhibitors. Despite this new agent being approved, several guidelines continue to suggest PCC administration for life-threatening bleeding associated with factor-tenet inhibitors due to the lack of comparative trials between what is considered the standard of care, PCCs, and indexinet-alpha. Although many practitioners feel comfortable using PCC for factor-tenet inhibitor-associated bleeding, this recommendation is based on few observational studies with a limited number of ICH patients. Given the current gaps in literature, the new reversal agent, the study group aimed to evaluate the safety and efficacy of PCCs for factor-tenet inhibitor-related ICH in a large multicenter cohort of patients. The study group comprised of 26 different sites, which were all designated as certified stroke centers, is currently completing a large retrospective multicenter cohort study evaluating the clinical outcomes between PCCs and indexinet-alpha. Due to the limited number of participating sites that are currently utilizing indexinet-alpha, as their preferred agent, data collection for the indexinet-alpha arm is ongoing, and the study reported here today is a pre-planned analysis of patients who were treated with PCCs for factor-tenet inhibitor-related ICH. Patients were included in the date range of January 1st, 2015 to March 1st, 2019. Here you can see the inclusion and exclusion criteria listed with the main inclusion criteria being that patients had an apixaban or rivaroxaban-associated ICH that warranted PCC administration, and that PCC was administrated at the participating hospital to ensure timing of when the dose was given. Notable exclusion criteria is withdrawal of life-sustaining measures within 24 hours of hospitalization, or they were enrolled in the prospective arm of indexinet-alpha. This study had two primary analysis groups. There was a hemostatic efficacy analysis and a safety analysis. The hemostatic efficacy analysis included patients with intracerebral, subarachnoid, or subdural hemorrhages who had at least one follow-up image within 24 hours of PCC administration to assess hematoma size. The primary efficacy outcome was the percentage of patients with excellent or good hemostasis defined by pre-specified criteria developed by Serode and colleagues, which has been used in multiple studies, and we'll talk about this criteria on the following slide. The safety analysis included all enrolled patients, including those who underwent neurosurgical procedures to capture the most comprehensive assessment of thrombotic risk associated with PCC, and thrombotic events included upper and lower extremity DVTs, pulmonary embolism, acute ischemic stroke, myocardial infarction, and any other documented thrombosis that occurred during hospitalization up to 30 days. Before we jump into the results, I do want to explain the rigor that went into defining the efficacy outcome, as I find this the major strength of this trial. For each patient included a licensed independent provider from each site with specialty experience in neurocritical care, neurology, or neurosurgery, reviewed all CT or MRI scans of the head and recorded hematoma measurements for patients with hemorrhages into multiple compartments. If their hemorrhage was in multiple compartments, the largest bleeding component was designated as the primary hemorrhage site. The provider evaluating the hematoma size recorded the measurements, but did not adjudicate the hemostatic efficacy outcome at that time that they were evaluating the image. The hemostatic efficacy outcome was done by the steering committee after all completion of data entry was done. A good or excellent hemostasis was defined by less than 35% increase in hematoma volume, and a poor or no hemostasis was defined by greater than 35% increase in hematoma volume. In total, 707 patients were evaluated with 663 included in the safety analysis. The most common reason for patients to be excluded from the safety analysis was that they did have life-sustaining care withdrawn within 24 hours. 433 patients were included in the efficacy analysis, and the most common reason that patients were excluded here was that they had a primary interventricular hemorrhage or an interventricular component of their primary bleed. And these patients were excluded just because the hematoma volume could not be evaluated. Moving to the results, we'll review the hemostatic efficacy first, and you'll see that the majority of patients were greater than 75 years of age and on anticoagulation for atrial fibrillation. About 54% of the patients were on apixaban, and the remainder received rivaroxaban. And 73% of the patients received four-factor PCC as compared to activated PCC. Here you can see the breakdown of the primary bleed type with a majority of patients having an intracranial hemorrhage or a subdural hematoma. They found that 81.8% of the cohort had excellent or good hemostasis, with 18.2% having poor or no hemostasis. In the 79 patients who were deemed to have poor or no hemostasis, 74 of those cases were identified on the first follow-up image. In-hospital death occurred in a total of 53 patients, and it was more common in those with poor hemostasis. And this difference was statistically significant. As you know, in neuroinjury studies, we don't usually like to look at hospital death. We like to look at more functional outcomes. However, this was the best long-term outcome that we could evaluate in a retrospective study. Moving to the safety analysis, here you can see the breakdown of patients was very similar to that of the efficacy arm. And again, the most common bleed type was intracranial hemorrhage followed by a subdural hematoma. 25 patients, or 3.8% of the cohort, had a thrombotic event. There were 15 DVTs. All of these events were lower extremity, except for one upper extremity DVT. Eight patients did have an acute ischemic stroke found on repeat brain imaging. Seven of these scans were done because the patient had worsening mental status. It is important to note that all patients who had an ischemic event, ischemic stroke, did have atrial fibrillation. Two patients had a myocardial infarction, and these were diagnosed by elevated troponin, and there were no other symptoms or no cardiac interventions done. And one patient had a PE, which was noted after worsening respiratory status. Additionally, the majority of these events, or 85%, occurred within 14 days of PCC administration. As pharmacists, I know we're all asking, well, what product and dosing did they use? The majority of patients, or 77%, received four-factor PCC with the remaining receiving activated PCC. The initial median PCC dose, or four-factor, was about 43.8 units per kilogram, and that of activated PCC was 26.7. The median time to PCC administration from hospital presentation was 2.6 hours, with an interquartile range of 1.5 to 4.3 hours. Additionally, a second dose of PCC was administered in 34 patients, or 5.1% of the population, and the details of the repeated dosing and the clinical reasoning of that is listed in the supplemental data, and it is very interesting, and I encourage you to look at it, but we don't have time to discuss those with the time given. In conclusion, you can see that they report a similar rate of good or excellent hemostasis as reported in the ANEXA-4 trial. Here, patients who received PCC in the fixed ICH study had an excellent or good hemostasis rate of 81.8%, and in the ANEXA-4 trial, patients with ICH had an excellent or good hemostasis rate of 80%. A notable difference was the thrombosis rate between these two trials, with the fixed ICH study having a 3.8% thrombosis rate, and that of ANEXA-4 of the entire population was 10%. I believe a possible difference in the thrombosis rate could be the retrospective nature of the fixed ICH study and the fact that those events were simply not found on a retrospective chart review. I do think we have to take these results into consideration, both efficacy and safety with the reported dosing that was used. So as a reminder, the four-factor dosing was around 50 units per kilogram, and that of the activated PCC was about 25 units per kilogram, and that's important to keep in mind when you are comparing this to the ANEXA-4 trial. Also, another limitation of this study is that we do not know the particular dose or the last time that the patient received their factor Xa inhibitor, so that's something that we should also take into consideration. I do believe, though, that this study provides valuable, pragmatic insight into the clinical effectiveness of PCCs that are observed in clinical current practice. However, I do think that a randomized controlled trial evaluating the clinical efficacy of what we call standard of care PCCs in comparison with indexinet-alpha and factor Xa inhibitor-related ICH is needed, and I think we're all anxiously awaiting the indexinet-alpha arm of this study to be completed. So we'll move to our first polling question. Give us a second to transition over. So the question is, how does, and for the staff, I'm having a hard time reading the instructions to the attendees because it's not showing up on my screen, but the question is, how does the FIX-ICH study change your practice for patients who present with a PIXABAN and RIVAROXABAN-related ICH? And the options are, A, no change, I will continue to use indexinet-alpha. B, no change, I will continue to use four-factor PCC. C, I now feel more comfortable utilizing four-factor PCC. Or D, I now feel less comfortable utilizing four-factor PCC. And the answer is C, no change. A, I now feel more comfortable utilizing four-factor PCC. Or D, I now feel less comfortable using four-factor PCC. Or E, other. And I think this will be a great question for us to discuss later in the continuing conversation or after the presentation. I'm not sure I'm seeing. There's some answers coming through. So, again, I think that the audience can see the results coming through a little easier than I can, but it looks like the most common answers at this point are B and C, which are no change, I'll continue to the four-factor, or I now feel more comfortable. And again, this is a question where there are no correct answers, and I agree that, we'll all have a lot to discuss about this as we talk more about it. But I do hope that this is a very large study of specifically ICH patients in which we looked at PCC dosing four-factor 10A inhibitor bleeds. I think that if you were already using four-factor PCC, this kind of gives you some more robust literature to support your decision. And if you weren't, I hope that you do feel comfortable, because I think that the criteria that they used to evaluate the hemostatic efficacy was very robust, as I mentioned in the beginning. And I think that even though it was a retrospective evaluation of that, you can't change the images, right? And we know exactly what those images look like and had independent providers actually evaluate that and measure those hematomas. So, I think that that's probably the strength of this trial and should give you a little more encouragement and support from the literature standpoint that you could use that confidently. So, I'm going to move on to the guidelines for the acute treatment of cerebral edema in neurocritical care patients. And this guideline was published in Neurocritical Care in 2020. As you all know, the acute treatment of cerebral edema and elevated intracranial pressure is a very common issue in patients with neurologic injury. Until now, we have not had a comprehensive guideline to address how we treat this neurologic phenomenon. And therefore, the Neurocritical Care Society set forth to create a guideline that evaluates the role of hyperosmolar agents, corticosteroids, and select non-pharmacologic therapies in acute treatment of cerebral edema. The methods of this guideline are listed here. The Neurocritical Care Society recruits experts in neurocritical care, including physicians, nursing, and pharmacy representatives. The group generated 16 clinical questions related to the initial management of cerebral edema and various neurologic insults using the PICO format. A research librarian executed a comprehensive literature search through July of 2018. And the panel screened and identified the articles for inclusion. The panel used the GRADE methodology to categorize the quality of evidence as high, moderate, low, or very low based on their confidence that the findings of each publication approximate the true effect of therapy. You'll find the GRADE of evidence key in the upper right hand corner of the slide. And the box recommendation of that color will correlate to the level of evidence that the expert is looking for. And the slide will show a list of all the evidence that the experts rated that recommendation. I have not included all 16 questions in this presentation as we don't have time to discuss them all. But I have pulled a few different recommendations that we can discuss throughout our time allotted. So the first question that I have mentioned is that for subarachnoid hemorrhage, they do recommend symptom-based bolus dosing and hypertonic saline rather than sodium-based dosing for the management of the ICP. And as you know, everyone in neurocritical care loves their sodium goals. But perhaps that's not the best way to manage intracranial pressure management in subarachnoid hemorrhage patients based on their literature review. For traumatic brain injury, the experts recommend with a low level of evidence that hypertonic saline should be used over mannitol for the initial management of elevated ICP in patients with TBI. They also know that mannitol is also an effective alternative. And they do encourage us throughout the guidelines that neither mannitol or hypertonic saline should be given with the expectation of improving neurologic outcomes. For acute ischemic stroke, they recommend utilizing either hypertonic saline or mannitol for the initial management of ICP or cerebral edema. They also suggest that you should consider administering hypertonic saline if your patient failed to respond to mannitol if that was given first. And this is an important recommendation that I want to mention. And they found with a low level of evidence that you should not use prophylactic scheduled mannitol in acute ischemic stroke due to the potential for harm. Two large retrospective cohort studies evaluated for this guideline reported an increase in risk of death at 30 days or greater functional dependency with prophylactic use of scheduled mannitol doses. The studies that were included could potentially be skewed by the prophylactic dosing scheduled in the most critically ill patient. However, the treatment bias could not be fully accounted for. For intracerebral hemorrhage, the guidelines suggest with a very low level of evidence that hypertonic saline can be used over mannitol for the management of ICP. However, they do suggest that either bolus dosing or sodium targeted concentrations is appropriate for the administration of hypertonic saline in intracerebral hemorrhage patients. And with a moderate level of evidence, the guidelines recommend against the use of corticosteroids to improve neurologic outcome in patients with ICH due to the potential for increased mortality and infectious complications. A 2005 Cochrane review that was included assessed the impact of corticosteroids on neurologic outcome in patients with ICH compared to placebo or standard of care controls. They found no evidence to support the use of corticosteroids and highlighted a potential for harm in these patients, including infectious and diabetic complications. Another trial reviewed even found a higher mortality in those patients in which dexamethasone was used. For bacterial meningitis, they do recommend the use of dexamethasone, the 10 milligrams IV, every six hours for four days to reduce the neurologic sequela associated with patients in community-acquired bacterial meningitis. And they do offer alternative dosing for patients with low weight at 0.15 milligrams per kilogram. And importantly, they note that patients should have the dexamethasone given with or before that first dose of antibiotics. When it came to hyperosmolar therapy, there was simply not enough published literature in the context of community-acquired bacterial meningitis to state which one would be preferred. And for our medical ICU colleagues, I've kind of thrown in this hepatic encephalopathy recommendation for you. They note that with a very low level of evidence that utilizing either hypertonic saline or mannitol is acceptable for the management of those patients. There just simply wasn't enough literature one way or the other to support one versus the other for the treatment of intracranial pressure in hepatic encephalopathy. And in conclusion, I do think these guidelines are a great first step to help determine how to treat patients with cerebral edema or increased ICP. I think they consistently say that hyperosmolar therapy may be helpful in reducing ICP, but they do not help improve the long-term neurologic outcomes of these patients. Again, corticosteroids appear to be helpful in reducing cerebral edema associated with bacterial meningitis. However, they could be harmful in patients with intracranial, or excuse me, ICH. And then importantly, I think that there's a dire need for high-quality research to better inform clinicians of the best options for individualized care in patients with cerebral edema. As we all know, this is a very difficult patient population to study or neurologic injury to study because cerebral edema and the various types of neurologic injury are very different. So cerebral edema with ischemic stroke is very different than cerebral edema with traumatic brain injury. And so it's very difficult to get good quality evidence for cerebral edema, but I think this is a good first step specifically for our patient population. And with that, I will hand it back over to our moderator, Dr. Barreto. Thank you so much. That was an excellent presentation. There's a lot to unpack there. I think in the interest of time for this section, we're going to move straight into Dr. Johnson's presentation, but I want to encourage everybody to start submitting some questions into the chat in the audience response. We are going to have a continuing the conversation after this session. So this will go until 10, so we can make sure to have some really good, lively discussion about some things that you noticed about that study. So next step, looking forward to Dr. Johnson's presentation and take it away. All right. Good morning, everyone. As mentioned, I will be providing the updates in trauma. The objective of this presentation is to describe management strategies to optimize care in our trauma patients. A list of abbreviations is provided here for your reference. Traumatic brain injury accounts for 2.8 million emergency department visits, hospitalizations, and deaths in the United States annually and is associated with a risk of coagulopathy ranging from 10 to 97%. Screening in our TBI patients may include standard assays such as INR or PTT, which will provide a quantitative assessment at a single point in time. Otherwise, screening may also include the use of viscoelastic assays such as thromboelastography, which will provide a more holistic functional analysis of the coagulation process over a period of time. So when we think about our general trauma population, we think about coagulation activation, hyperfibrinolysis, and consumption coagulopathy. And when we think about our TBI population, coagulopathy is equally as concerning. So we recognize that hypocoagulability is associated with hemorrhage. Meanwhile, hypercoagulability is associated with ischemia. And when we think about our TBI population, again, studies have demonstrated a correlation between TBI severity and coagulopathy with rates of coagulopathy in our severe TBI population as high as 60%. Additionally, when TBI is associated with coagulopathy, these patients are known to have worse outcomes. So a study by Talving and colleagues actually found a tenfold increase in mortality among TBI patients who did develop coagulopathy during hospitalization. So my polling question for the audience today is with regards to the TBI population. In your patients presenting with severe TBI, which of the following recommendations would you provide? A, tranexamic acid or TXA, one gram bolus followed by a one gram infusion. B, desmopressin or DDAVP, 0.3 micrograms per kilogram, infusion over 30 minutes. C, TXA, two gram bolus without a maintenance infusion. Or D, need more information prior to providing a pharmacologic recommendation. So for this polling question, again, the instructions are available to you at the top of the screen. It looks like we have a few results coming in, but we'll wait for some additional results before we move on. All right, so it looks like we have some good variation of results here. Really the purpose of this question here was to prompt a discussion. We recognize that there's a lot of literature showing various results. And what we'll do on the coming slides is discuss some of the literature that really coincides with some of these decisions we may need to make as clinicians. Looking at the majority of responses, it looks like most of the audience agrees we do need some more information. So with that, we'll move ahead on to the next slides. So looking back over the last decade when it comes to data and literature and trauma, I think we are all familiar with the CRASH-2 trial from 2010 which evaluated over 20,000 patients aged 18 years of age who presented within eight hours of traumatic injury who had or were at risk of hemorrhage. The interventions provided were TXA one gram bolus followed by a one gram infusion or placebo. And the authors of this study found that TXA was associated with a reduction in in-hospital death within four weeks of injury. While their secondary outcomes didn't differ between groups, they did find that the time to TXA administration was important and administration within three hours was really the most significant in reducing in-hospital mortality. Following the CRASH-2 trial, we had the CRASH-3 trial in 2019 which aimed to assess the use of TXA in our TBI patient population. Here more than 12,000 patients aged 18 years of age or older with traumatic brain injury being moderate to severe in nature or intracranial hemorrhage with no major extracranial bleeding and whose injury occurred within three hours received either TXA with the same dosing from the CRASH-2 trial or placebo. With regards to the primary outcome, they did not find any difference between groups in in-hospital head injury related mortality at 28 days. But when they looked at death within 24 hours, they did find a reduction in death in the mild to moderate TBI group, especially when TXA was administered early. Moving forth to some large trials from 2020, we had the resuscitations outcome trial which really looked at the role of TXA in TBI. And this was investigation of two dosing strategies of TXA. Here patients aged 15 years of age or older with moderate to severe TBI who were not hypotensive and presented within two hours of injury received either standard dose TXA or a TXA two gram bolus without maintenance infusion compared to placebo. For their primary outcome, they did not find any differences between TXA administration in placebo when it came to favorable neurologic outcomes at six months. When they looked at mortality overall, they did not find a difference between groups and the mortality rate was actually similar to that of the CRASH-3 trial, but in their combined adjusted and modified outcomes, in their combined adjusted analysis, they did find that TXA, particularly the bolus only dosing strategy was associated with a reduction in 28 day mortality. While there was no difference in thrombotic events, one thing to note from this study was that the bolus only being the two gram bolus was associated with an increased incidence of seizures. Lastly, we had the STAMP trial which really investigated the role of TXA during pre-hospital transport in patients at risk of hemorrhage. So here patients were aged 18 to 90 years of age who presented within two hours of traumatic injury and again had similar systolic blood pressure and heart rate parameters from the CRASH-2 trial. What's unique about this study is the various TXA dosing strategies that were evaluated. So first was a TXA one gram bolus without infusion. Second was our standard TXA bolus and maintenance infusion. Three was a different strategy with regards to bolus dosing. So the third arm received two TXA one gram boluses followed by maintenance infusion for a total of three grams and all of these arms were compared to placebo. When they looked at 30 day mortality, there was no difference between the TXA groups when compared to placebo. When they investigated the different regimens, they did find a reduction in 30 day mortality for those that received the repeat bolus dosing. Additionally, there was no difference in secondary outcomes. So in summary, when we think about TXA, the mortality benefit in our TBI population seems to be less profound than our general trauma population. Although there may be potential benefit in mild to moderate TBI in those presenting with severe shock, especially as well as in those presenting early within two hours from traumatic injury. When we think about different dosing strategies for TXA, we may consider more aggressive bolus dosing. So whether it's the two gram bolus or the repeat bolus, these were associated with reductions in mortality or potentially improved outcomes. But with that said, we do have to take into account the potential for adverse reactions. So if TXA isn't our miracle drug with regards to reducing mortality in TBI, then maybe Desmopressin or DDAVP is. Desmopressin is a synthetic analog of antidiuretic hormone with hemostatic effects that may be beneficial in the management of TBI-induced coagulopathy. And this really is through an increase in release of factor VIII as well as von Willebrand factor, but it does also cause an increase in tissue plasminogen activator. So studies have shown that Desmopressin can stabilize platelet dysfunction, but this duration of effect may be limited. Additionally, studies looking at patients with TBI, particularly those with pre-injury antiplatelet therapy have demonstrated a reduction in hematoma expansion. So before we go on to the next slide, I just want to add some information regarding platelet function. So when we think about Desmopressin and we think about platelet function, what we often think about is adenosine diphosphate or ADP inhibition. So looking back at some articles, a cardiac surgery study from 2004 did find that an ADP inhibition greater than 60% predicted severe coagulopathy requiring multiple transfusions. Additionally, when we think about our TBI population, we recognize that severe TBI is associated with an increase in ADP inhibition. So increased severity correlates with increased ADP inhibition. And this was really reinforced by a study by Daley and colleagues in 2016, which looked at 90 TBI patients and found that there was a significant correlation between increase in in-hospital mortality amongst patients who had greater than or equal to 60% ADP inhibition on TAG. So the study that I'd like to focus your attention to now is titled Desmopressin is a transfusion sparing option to reverse platelet dysfunction in patients with severe traumatic brain injury. This was a single center retrospective chart review that aimed to determine if Desmopressin corrects platelet dysfunction similarly to platelets in severe TBI. The primary outcome was ADP inhibition. So correction being greater than or equal to 60%, again, was defined as the platelet dysfunction. And secondary outcomes included mortality and lengths of stay. Moving your attention to the right-hand side of this slide, this was their flow sheet for enrollment into the study and intervention. So amongst those who are identified as having platelet dysfunction defined as greater than or equal to 60% ADP inhibition on the admission TAG, they received either Desmopressin 0.3 micrograms per kilogram IV infusion or platelets. Following intervention, they did obtain a second TAG and further interventions were determined based on the results of that second TAG. Those included had severe TBI, which was defined as an abbreviated injury score of the head greater than or equal to three, had platelet dysfunction identified on the TAG, had received platelets or Desmopressin and had a repeat TAG post-intervention. Exclusion criteria are listed here for your reference. When we look at the demographics between groups, there's two things to note. There was a larger number of white patients in the platelet group, but the Desmopressin group had a higher injury severity score. Additionally, I'd like to note that there was no difference in pre-injury antiplatelet therapy prior to injury between groups. So with regards to their primary outcome being the correction of ADP inhibition, looking at the right-hand side of this slide, what they found was that Desmopressin actually corrected ADP inhibition to a greater degree than that of the platelet group. So just for reference, 57% of the patients in the Desmopressin group achieved an ADP inhibition less than 60% compared to only 32% of patients in the platelet group. Additionally, when they evaluated the TAGs to look for other corrections, they found that the platelet group was actually associated with an increase in, or excuse me, a decrease in SP time or time to first detectable fibrin, as well as an increase in the angle, maximum amplitude and G value, which correlated with an increase in platelet activation and clot strength. For secondary outcomes, they found no difference in length of stay, but they did find that the Desmopressin group was associated with the higher rate of mortality, and the authors of this study contributed that to the higher injury severity score. So while Desmopressin did not reduce mortality when compared to platelets, it was effective in reversing platelet dysfunction. So when we think about our TBI-induced coagulopathy, really we associate this with lesion, progression, mortality, and worse outcomes. With regards to pharmacologic therapy, really no agent has shown a significant benefit in reducing mortality. So TXA may be used early, particularly in our patients with mild to moderate TBI or those presenting with severe shock. On the other hand, Desmopressin may be considered for patients with severe TBI, including those without pre-injury antiplatelet therapy. Both of these agents may be considered favorable when compared to blood products, simply due to the reduction in risk of transfusion reactions, infection, or cost. And when we think about future directions, really with regards to TXA, we've had well-powered prospective studies that have continued to show no benefit in moderate to severe TBI. So will there ever be benefit? Well, I guess we'll just have to wait and see. With regards to Desmopressin, I think additional studies really are needed to evaluate its role in TBI management. And lastly, there may be consideration of alternative biomarkers or standardization of use of viscoelastic assays, particularly at institutions that may not use these routinely. So that is the end of my presentation, the blunt truth, updates in trauma. I will pass the mic over to Dr. Barreto, our moderator. Thank you so much, Dr. Johnston. I want to echo what I said earlier. Please keep the audience response questions coming in on the chat. We have some really good questions about both of the talks so far, and we'll make sure that we have some time to get to these and many others in the last section here, where we continue the conversation. But I want to give plenty of time to Dr. Bissell to give us some updates on pulmonary diseases and the critically ill. So take it away, Brittany Bissell. Thank you, Erin. Thank you everyone for hanging around with me for the third session of three today. I've been tasked with talking through some of the pulmonary updates for the past year with y'all. I'm sure as this group can imagine, having a conversation that's pulmonary related that is not all about COVID-19 is a little bit challenging, but I did want to make sure to talk both about some of the pandemic concerns, as well as the populations that we see quite commonly outside of the pandemic, specifically acute respiratory distress syndrome. And so today I'm going to be talking to you about the use of glucocorticoids or steroids in some of these key populations. And really want to have a discussion about this literature and hear from everyone of how you're currently managing a vast number of these patients. So I think it's difficult to talk about 2020 and steroid publications in 2020 without having a brief discussion as to where we came from as it pertains to the use of steroids and ARDS. Now we know back in the 1970s, we started to see pretty strong preclinical data that showed a potential benefit with the use of steroids and reduction of inflammation and clinically pertinent parameters as well, such as changes in pulmonary vascular resistance and alveolar capillary permeability. And so we saw early studies seek to look for the prevention of ARDS with the use of steroids. Now, unfortunately, a lot of those studies fell flat, but that didn't stop the momentum for steroids. So we also saw the use of steroid studies for early treatment, specifically of patients with an already confirmed diagnosis of ARDS. Now, similarly, early trials did fall a little flat, but thanks to Anand and colleagues and their publications surrounding the use of steroids and septic shock, a lot of momentum continued through steroids and continues, I feel like to this day, for the use of steroids in a vast number of populations. And so one of the key studies I think a lot of us think of when we talk about early treatment of ARDS and the administration of steroids is the first Miduri study, which did show a benefit in ventilator-free days and improvement in lung injury scores with the use of steroids. And we haven't stopped there, right? So there's been additional studies that have looked to utilize steroids for late ARDS patients as well. And I think of a couple of key studies when I think of late ARDS and the use of steroids. The first of which was by Miduri and colleagues enrolling patients that had had ARDS for seven days, a maximum of 21 days, which a study was unfortunately stopped early after just a small number of patients because of a signal of harm in patients that were receiving placebo. Now, what was most interesting about this placebo group is that a significant portion of them had had crossover into steroid receipt. And so what the potential conclusion of the study is that this late addition of steroids in the placebo group, specifically after 10 days, was a potential indicator of harm or potentially a risk factor for mortality in this group. Now, the other key study, especially when we think of harm, comes from the NHLBI study that produced very similar inclusion criteria. And now this study, while they enrolled patients after seven days again, maximum of 28 days, they showed a benefit with the use of steroids, specifically on ventilator-free days at 28 and 180 days. Now, the problem with this study is in their subgroup analysis in patients that were enrolled in this study after day 13, they saw an increase in mortality with the use of steroids. And from here, I think we've lost a little bit of momentum, but not all when it comes to the use of steroids for ARDS. We started to see more specific populations and etiologies be called out, such as community-acquired pneumonia and different viral diseases, and most pertinently now, COVID-19. And so to find some confirmed conclusions as it pertains to the use of steroids when 2020 was just beginning, I think there's, again, more questions than answers in all probably aspects of their use. The early prevention trials, to be quite frank, were not powered really to determine a difference in ARDS incidents and had a lot of heterogeneity really inhibiting any type of pooled analysis within them. Now, the early steroids or the use of steroids in early ARDS probably has the best evidence, or I think the evidence that a lot of our clinicians feel most comfortable with. But at least in my experience, I think this potential signal of harm, especially for ARDS or late ARDS and the administration of steroids then, has really prohibited a lot of individuals from using steroids within this population at all. And now, I think it does worth mention that when we talk about the potential harm with late steroids, there are considerations and to the studies that we've seen harm with. The first of those studies was stopped early, really were extrapolating data based off of eight patients that saw harm in that first majority study showing mortality in that placebo group. And then the other analysis that showed harm was a subgroup analysis of a trial that actually did show benefit when defining ARDS after defining late ARDS as greater than seven days. So again, there's a lot of questions that remained. And that brings me to the first study that was published in 2020, hoping to answer some of these questions was the DEXA ARDS study published very early in the year. This was a multi-center randomized control trial that was performed to patients meeting ARDS criteria in 17 different Spanish ICUs. They enrolled about 277 patients. And it is significant and important to note that a solid portion of these patients had pneumonia or sepsis as their underlying etiology. Now, here we brought to light the use of dexamethasone. And so the steroid regimen within this trial was 20 milligrams of dexamethasone daily for the first five days, followed by 10 milligrams daily for the last five or until extubation. Now, important to note, patients must have had a P to F ratio of less than or equal to 200. They enrolled patients at 24 hours, but no later than 30 hours after onset of ARDS. Now, when we look into the results of this study, they actually only enrolled about 27% of eligible patients, which leads us to the rationale for why they had to terminate the study early based on their overall enrollment. So the study was stopped after hitting about 88% of their sample size. And the authors do a good job of explaining the why as it pertains to the study stop. A lot of the centers in which we're enrolling for this study started having a high incidence of off-protocol steroid use. They specifically cite the year 2017. They started to see a high implementation of steroids for septic shock and pneumonia. And because of that, those patients were not eligible for inclusion into this study. And so the study was stopped early. For the patients that were included within the study, there wasn't a lot of off-protocol steroid use in the protocol, sorry, in the standard of care group, only about two patients. So otherwise, the data is pretty promising in regards to who they were able to enroll after exclusion of those other patients. When we look at rates of concomitant therapies, they were similar between patients that received dexamethasone versus those that didn't, about 60% of patients receiving paralysis, a quarter of patients receiving prone positioning, and less than 10% going on to extracoreal lung support. Now, if we look at adverse event rates, again, not different between groups, which is promising, no rates of hyperglycemia, new infection or barotrauma, or no difference in those rates between the two groups. Now, what was different and what is worth mentioning are some of the strong clinical differences that were found in patients that received dexamethasone. So specifically patients receiving dexamethasone had a significant increase in ventilator-free days, 12 days versus seven and a half with standard of care. The mean duration of the vent for those patients on dexamethasone was about 14 days compared to 19 and above with the standard of care group. The authors do cite some improvements in organ failure assessment scores and P to F ratios, but the other big clinical outcome I think worth mentioning is this difference in all-cause mortality. The dexamethasone was associated with a 21% mortality rate compared to the 36% that was seen in the standard of care group. Now, moving on to the second probably key study looking at steroids for respiratory diseases in 2020 was that from the recovery group. So for those who may not know, which I highly doubt if anyone on this call today, but the recovery group has really taken on this large multicenter study that has tried to tackle the treatment approaches for the COVID-19 and SARS-CoV-2 over the past year. And so they actually produced this preliminary report early in 2020 as well of the data that they were able to pull from their randomized controlled trial in 176 hospitals within the study group. Now, there were about 9,300 patients that had underwent randomization at the point of this study inclusion, but 6,245 of those patients were pertinent to this study specifically. Now, talking about pertinence of the study, I think it's really important to note that 15 to 16% of these patients had mechanical ventilation, which is obviously a consideration for us clinicians, but most of the time we're seeing the patients once they're already on the vent. For those patients that were enrolled into the study, most patients had about eight or nine days since they started having positive symptoms. And most of the patients have been in the hospital for about two days. The dose of dexamethasone that was used in this study specifically was six milligrams daily for up to 10 days or until hospital discharge. Similarly to the dexa-ARDS study, we did see a significant improvement in mortality with the use of steroids in the recovery trial. Now, again, this is just a preliminary report, but we do have confidence in these numbers as 99% of the patients, at least at time of this report, had their 28-day outcomes known. When we looked at specific subgroups of the cohort, particularly based on level of supportive oxygenation that was required, we did continue to see an improvement in mortality in patients that were receiving mechanical ventilation and those that were receiving supplemental oxygen that was not mechanical ventilation. Now, this difference didn't hold true in those patients that were not receiving any level of oxygen supplementation at the time. When it comes to the invasive mechanical ventilation group, the mortality in the group in this study was 41% within the placebo group or standard of care group, which was double what had been reported in some studies at the time of this publication, but still fairly significant compared to the 29% mortality rate for patients on the vent receiving dexamethasone within this study. One interesting result of this study, which really happened by chance, was a significant difference in the baseline age between the two groups, about a 10 to 11-year age difference between standard of care versus dexamethasone. And so the study authors did go on to do a subgroup analysis to look at the impact of dexamethasone use based on the patient age or subject age. And what they tended to see was the most of the benefit occurred in those patients that were less than 70 years old despite the fact that the dexamethasone group was actually much older in comparison to the standard of care during the study period. When looking at days since symptom onset, we see that the benefit really remains in those patients that have had symptoms since greater than seven days, where that significance really crossed that threshold of one when we look at those patients with symptoms of equal to or less than seven days. Now, we have to take a moment to pause and think of where we're at now when it comes to the administration steroids. I do think that we have probable cause to include dexamethasone within the treatment course for both of these populations. But I do think there are some questions that remain that are worth having discussion on. Now, specifically, I think it's important to reflect back on some of that first preliminary data and the original mechanism of action that was seen back in the 1970s that really focused on attenuation of inflammation and the level of inflammation that is seen within these patients. Now, there is the possibility that benefit in specific populations may need to have an emphasis or is emphasized based on the patient's phenotype. And where we've seen this play out is really in the ARDS population and the different phenotypes that have been noted within this group. We've seen latent class analyses that have been published that have shown two specific phenotypes of ARDS, both a hypo-inflammatory and a hyper-inflammatory ARDS. And this has seemed to matter because when those populations or those phenotypes have been applied to previous studies of ARDS treatment, there's been a difference in outcomes based on which phenotype the patient fell into. And I think it's quite intriguing that Liesman and colleagues this year kind of extrapolated that and continued that assessment of phenotypes into a broader population of some of these quote unquote inflammatory diseases. So Liesman and colleagues looked at a biomarker analysis both in ARDS patients of either phenotype, a COVID-19 patients and patients with Trucetic Heinz storm. And what was really intriguing about these results and this is when we really started to see that when we think of COVID-19, when we talk about some of our common biomarkers, especially interleukin-6 and interleukin-8 for this inflammatory response, those tend to be much more attenuated than COVID-19 when compared to even the hypo-inflammatory phenotype of ARDS. Now on the alternative, what we tend to see to be much higher, which I think is probably not much of a surprise to those of us seeing these patients at bedside is the higher levels of acute phase reactants. So specifically in this study, the C-reactive protein as seen with COVID-19. Now, I don't think that's too surprising. We know that the T lymphocytes are directly susceptible to SARS-CoV-2 and that they can be depleted in COVID-19. And we know that we may potentially have a resulting hypoimmune state with this virus-mediated tissue damage and dysregulated inflammation that is pretty consistent with what we're seeing here. Now, then the question becomes, what is the mechanism of action in patients that are receiving steroids for COVID-19 if it's not an IL-6-mediated disease or mechanism of action? Is there suppression of a late-onset fibrosis that prevents some of this irreversible lung damage and an alternative mechanism of action of corticosteroids? So a lot to be answered as far as the inflammatory profiles first, but also the mechanism of action and how much inflammation really matters with these patients. Of course, I also think you have to mention the fact that a lot of these analyses have very much been focused on a proteanomic level. Steroids specifically and some of our other treatments definitely have genomic and transcriptomic considerations that probably need to be made, especially when we're talking about the differences in patients across these groups. And so definitely some areas for future research in a lot of different ways. So for me, in summary, when talking through the role of corticosteroids, I think it's pretty definitive that patients with ARDS, secondary deceptive shock or pneumonia, should receive corticosteroids. And with COVID-19, I do think by the time that we're seeing them within the medical ICU or the alternative ICUs, it's probably time for steroids as well. I think dexamethasone is preferred over alternatives, if for me, just on ease alone, but I'm open to discussion on this with some of the previous methylprednisolone studies. And the dosing selection should be made based on level of oxygen supplementation. So for me, this is a question that we're really asking a lot at my institution and what dose of dexamethasone we're using, if we're using it, and specifically when we talk about patients with COVID-19 and ARDS. So I wanna take a minute to poll the audience about what you all are doing or what your thoughts are surrounding the use of corticosteroids. So in an adult patient admitted to your ICU, receiving mechanical ventilation for 24 hours with a P to F ratio of less than 200 despite optimal ventilator settings with a positive SARS-CoV-2, do you start steroids? And if so, what regimen? Instructions still are at the top of the slide. Potential answers here, no steroids, the use of dex six daily, dex 20 milligrams daily, methylprednisolone one milligram per kilogram or methylprednisolone two milligram per kilogram or an alternative regimen. Okay, so I'm starting to see a big shift towards the six milligrams daily. Less so for the methylprednisolone. And no one said 20 milligrams daily of dexamethasone. I'm surprised. I have a lot of physicians at my institution that are trying to push for 20 milligrams daily. So again, I think like the other presenters, as we talked through this today, you know, I think that there's probably not a perfect answer as there's not a study really that fits exactly this population. But I do think that, you know, the use of six milligrams daily of dexamethasone is definitely a possibility and definitely a plausible for this population. So that's it for me today.

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