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 Megan Reck, Emergency Medicine Clinical Pharmacist and PGY-2 Critical Care Pharmacy Residency Director at Loyola University Medical Center in Maywood, Illinois. I will be moderating today's webcast. A recording of this webcast will be available to registered attendees. Log into mysccm.org and navigate to the My Learning tab to access the recording. A few housekeeping items before we get started. There will be a question and answer session after each of today's speakers. To submit questions throughout the presentation, type into the questions box located on your control panel. You will also have an opportunity to participate in several interactive polls. When you see a poll, simply click on the bubble next to your choice. SCCM provides the following disclaimer. This presentation is for educational purposes only. The material presented is intended to represent an approach, view, statement, or opinion of the presenter, which may be helpful to others. The views and opinions expressed herein are those of the presenters and do not necessarily reflect the views or opinions of SCCM. SCCM does not recommend or endorse any specific test, physician, product, procedure, opinion, or other information that may be mentioned. And now I'd like to introduce our speakers for today. Each will give a 15-minute presentation followed by a Q&A session. Our first presenter today is Catherine Tinkey, PGY-2 critical care resident at Detroit Receiving Hospital in Detroit, Michigan. Our second presenter is Ashley Camp, our PGY-2 critical care resident at Duke University Hospital in Durham, North Carolina. And our third presenter is David Raghunanan, PGY-2 critical care resident at Tampa General Hospital in Tampa, Florida. And now I'll turn things over to our first presenter. Hello. Thank you for that introduction. Like Megan mentioned, my name is Catherine Tinkey, and I will be talking today about the trial dexmedetomidine for reduction of atrial fibrillation and delirium after cardiac surgery, a randomized placebo-controlled trial, which is shortened as the DECATE trial. First, I would like to touch briefly upon some background for delirium and postoperative atrial fibrillation, which is abbreviated as POAF in the literature and throughout this presentation. Postoperative atrial fibrillation is a relatively common complication in patients recovering from cardiac surgery, occurring in approximately 35% of cases. And delirium is relatively common as well, estimated to occur in 20% to 50% of cases. The risk factors for postoperative atrial fibrillation and delirium have some overlaps, including advanced age and history of multiple comorbidities, such as heart failure and complex surgical procedures. Preventing postoperative atrial fibrillation and delirium are important therapeutic goals because they each are associated with adverse patient outcomes. For example, both are associated with an increased risk for mortality, prolonged ICU and hospital length of stay, and increased healthcare costs. Here I have a short summary of the guideline recommendations we have for the prevention of postoperative atrial fibrillation in cardiac and thoracic surgery patients and the prevention of delirium. The prophylactic use of beta blockers, calcium channel blockers, and amiodarone are generally recommended to prevent postoperative atrial fibrillation, but unfortunately, there are no pharmacologic agents that are recommended or that have been proven to be helpful for the prevention of delirium. So why is there an interest in using dexmedetomidine in cardiac surgery patients? In the figure here, we can see that the stress response to surgical trauma results in an increased secretion of pituitary hormones and activation of the sympathetic nervous system. Dexmedetomidine agonizes central alpha-2 receptors, which are represented in green on this picture of the brain. This central alpha-2 agonism by dexmedetomidine decreases the release of catecholamines and thereby causes the familiar effects of bradycardia, sedation, anxiolysis, and analgesia. Thus, it is hypothesized to reduce the incidences of postoperative atrial fibrillation, delirium, acute kidney injury, and persistent pain in these patients. Dexmedetomidine is also thought to have anti-inflammatory effects, which has the potential to reduce the incidences of postoperative atrial fibrillation, acute kidney injury, and persistent pain. The prior literature regarding dexmedetomidine's role in this patient population is limited. For postoperative atrial fibrillation, there is an observational study that reported a 26% reduction in atrial fibrillation with dexmedetomidine used in cardiac surgery patients, and there was also a small prospective study that reported a 22% reduction. However, a later published meta-analysis found no reduction in atrial fibrillation associated with the use of dexmedetomidine. The literature for delirium is even more scarce, but a meta-analysis published in 2018 found that delirium was significantly reduced in cardiac surgery patients that received dexmedetomidine. That brings us to the DECADE trial, which was published in the Lancet in July 2020. The authors hypothesized that perioperative dexmedetomidine given for 24 hours would reduce the incidences of atrial fibrillation and delirium, which were the trial's primary outcomes, as well as reduce the incidences of acute kidney injury and persistent incision pain, which were the secondary outcomes. The trial was designed as a randomized placebo-controlled study that was investigator-initiated and conducted across multiple sites in the United States. It was a double-blinded parallel study with superiority outcomes, and the funding for the study was provided by Hespera Pharmaceuticals, which is the manufacturer for dexmedetomidine. Patients were included if they were 18 to 85 years of age scheduled for cardiac surgery with cardiopulmonary bypass that had a baseline heart rate of at least 50 beats per minute. There were several exclusion criteria that are listed here, but some notable exclusions included patients who used dexmedetomidine or amiodarone in the past 30 days, or who used clonidine in the past 48 hours, as well as patients with history of severe heart failure or history of atrial fibrillation in the past 30 days. The dexmedetomidine or placebo infusion was started prior to the first surgical incision at 0.1 micrograms per kilogram per hour. After cardiopulmonary bypass was discontinued, the infusion rate was then increased to 2.2 micrograms per kilogram per hour. And then finally, when the patient's surgery was complete, the infusion rate was increased to 0.4 micrograms per kilogram per hour. However, throughout the study, the infusion rate could be decreased at any time as needed for hemodynamic instability. Additionally, other agents for anesthesia and sedation, such as propofol, opioids, and betadine azepines, were allowed to be administered at the provider's discretion. The primary outcome of atrial fibrillation was identified by diagnosis from a blind anesthesiologist or anesthesiologist based on any episode that lasted at least 5 minutes or by clinical diagnosis. The patients were monitored on a 12-lane ECG for 5 days or until discharge from the hospital, whichever came sooner. For the other primary outcome of delirium, patients were assessed using the CAM-ICU assessment by blinded physicians and by the patient's nurse, who was also blinded to treatment assignments. As is customary for CAM-ICU assessments, the patient's RAS scores were first assessed to ensure that they were at an appropriate level of sedation with a RAS greater than negative 4. The secondary outcome of acute kidney injury was evaluated using the ACAM classification by assessing the most recent serum creatinine preoperatively compared to the highest serum creatinine postoperatively up to postoperative day 5. And the secondary outcome of persistent incision pain was assessed at 90 days using several standardized assessments. Safety outcomes were also assessed and included the incidence of bradycardia that required treatment, hypotension that required vasopressors or fluid bolus, as well as stroke, myocardial infarction, feet pain, dark poses, or pulmonary embolism, surgical site infection, and death. For the statistical analysis, they used an intention-to-treat method. The authors calculated a necessary sample size of 985 patients based on atrial fibrillation. They estimated that the control arm would have a 35% incidence of atrial fibrillation and that dexmedetomidine would lead to a 30% decrease in incidence. There was scheduled interim analysis for efficacy and futility at each 17% of sample size increase in enrollment. I also want to note that for the statistical interpretation, they maintained an overall alpha of 0.05, but they adjusted the p-values for significance using von Faroni corrections because there were two primary outcomes and two secondary outcomes. The p-value for significance was adjusted to 0.025, and then the primary outcome p-values were further adjusted to 0.022 for significance due to alpha spending for the interim analyses that were performed. Also noted by the authors was that they defined a priori that any significant difference in baseline characteristics would be adjusted for in all analyses. Now for the results. 3,357 patients were screened and 798 patients were randomized between April 2013 and December 2018. However, the study was stopped early due to futility after the final scheduled interim analysis. Table 1 of the study lists the baseline characteristics for the patients included. The population was mainly comprised of white males in their early 60s, nearly half of which used beta blockers prior to admission, but very few patients were using any other antiarrhythmics or digoxin, as you can see here. The only baseline characteristic that met the pre-specified cutoff for an absolute standard between groups was history of prior cardiac surgery. 10% of the dexmonetamidine arm and 15% of the control arm had undergone prior cardiac surgery, so this was adjusted for in all of the analyses. Table 2 represents the primary and secondary outcome results for atrial fibrillation. The results were very similar with an incidence of 30% in dexmonetamidine arm versus 34% in the control arm. Delirium incidences were also similar between groups, but trended higher in the dexmonetamidine patients at 17% compared to 12% in the control patients. The patients were analyzed for AKI by being classified as either having no risk for AKI versus having any stage of AKI. The number of patients having no risk for AKI was similar between groups with 89% in the dexmonetamidine group compared to 92% in the control group. And finally, for pain at 90 days, the results were again very similar with 27% of dexmonetamidine patients reporting pain versus 32% in the control arm. When analyzing these differences for statistical difference, although the delirium p-value was .026, the p-values were adjusted, as I mentioned earlier, and so the results were interpreted as having no difference between groups for any of these endpoints. Table 3 represented the results of some exploratory outcomes, and there was largely no notable differences in IC or hospital length of stay or any of the safety outcomes evaluated between groups, with the exception of clinically important hypotension, which is the fourth outcome listed here on this table. Clinically important hypotension, meaning that the patients required vasopressors or fluid bullets, occurred in 57% of the dexmonetamidine patients and only 36% of the control patients. In a postdoc analysis, the authors found that there was a potential relationship between clinically important hypotension and the incidence of delirium, which was also higher in the dexmonetamidine group. 58% of patients that experienced delirium had also experienced hypotension, but only 44% of those that did not experience delirium had experienced hypotension. The p-value for this interaction was .009. The authors concluded that the incidence of atrial fibrillation and persistent pain with dexmonetamidine were not different compared to placebo, and that dexmonetamidine worsened delirium and kidney injury, although not by a significant amount. So they recommended that dexmonetamidine should be used cautiously in cardiac surgery patients with attention to preventing hypotension, and that it should not be given with the expectation that it will reduce the incidences of atrial fibrillation or delirium. Now to provide some of my critique and interpretation of this study. First, I believe that this trial does have clinical relevance as it addresses an important therapeutic goal with commonly used agents that have limited prior evidence. The study design and methods I thought were very well done because at the randomized placebo controlled multi-center trial, this design provides some of the highest levels of evidence. However, the authors did not provide rationale or evidence for the dexmonetamidine infusion doses used or for the magnitude or timing of the rate changes. These doses were on the lower end of study dexmonetamidine doses, but because there was that significant hypotension and the dexmonetamidine arm noticed, higher doses likely would not have provided any additional benefits. I felt that the way the primary outcomes were measured was appropriate. Atrial fibrillation was diagnosed by a blinded expert after a clinically significant time point of five minutes. However, it could also be diagnosed by, quote, clinical diagnosis, which is reasonable but also rather vague, and it was not defined. For delirium, they used blinded CAM-ICU assessment, which we know is one of the most common and well-validated scoring tools for assessing the presence of delirium, with reported 93% specificity and 89% sensitivity. I also feel as though they used appropriate measures for their secondary outcomes. However, I did notice for the persistent incision pain at 90 days, there were many patients that were lost to follow-up. 27% of the dexmetamidine arm and 24% of the control arm did not provide data for this endpoint, which isn't a limitation for that assessment. The patient population assessed makes the results of this trial broadly applicable. The exclusion criteria ensured that patients with confounding baseline characteristics were not enrolled, but that did require the exclusion of some patients that are at higher risk, such as those with a history of atrial fibrillation and with heart failure. So, while I feel that the results can be broadly applied, it's important to keep in mind that some of these higher-risk patients were excluded. I also want to touch upon the potential for bias that, although Hesperia Pharmaceuticals did provide funding for the trial, they had no role in the study design or data analysis, so I did not perceive any bias. For the overall clinical interpretation, I think it's important to note just a few data points that were not assessed or reported on by the authors. The authors did not report the frequency of use of other sedatives, such as propofol, opioids, or benzodiazepines between the arms. So, these other sedatives could be confounders to the results. There also was no report on how the patients who did experience atrial fibrillation were managed between the arms, so this could be another confounder. I also wanted to note that the power was calculated based on incidence of atrial fibrillation, and it was not calculated for the other endpoints. So, of course, the trial ended early due to futility for meaning and significance for the atrial fibrillation endpoint, but we also don't know if power was met or if the other endpoints had futility in finding a difference, so these other results should be interpreted with some caution. So, that leads me to my final point that I wanted to mention, which is that the trial authors did specifically note in their conclusions that dexmedetomidine coerced delirium and AKI, but these were simply trends and they were not statistically significant. So, I just wanted to reinforce that trends that are not statistically significant can be hypothesis-generating for future study, but they should be interpreted with caution. So, the takeaway points that I wanted to leave with this trial are that this trial does provide us with evidence that dexmedetomidine is ineffective at preventing atrial fibrillation, delirium, AKI, or persistent pain in cardiac surgery patients, and it should be avoided or at least used with caution in this population, particularly in regards to hypotension. At my current institution at the Detroit Medical Center, I've spoken with our pharmacists that most often treat CT surgery patients, and the use of dexmedetomidine is not a common practice, so I will not be recommending any changes here based on this trial, but for future directions, I believe some more research is needed to prevent these adverse outcomes in cardiac surgery patients, particularly in regards to delirium, where we have no proven agent for prevention. So, now I would like to introduce some polling questions for the audience. First, I would like to ask how often have you used dexmedetomidine or seen it used in cardiac surgery patients? We have a breakdown here for you for over 75% of the time, 50 to 75% of the time, 25 to 49% of the time, less than 25% of the time, or you can respond if you typically don't treat this population. So, we'll just give a few minutes for responses. Okay, so it looks like we have a good mix here. There's 14% that do use it pretty regularly, but then we have a significant portion of people more so that don't use it at all, and some people don't treat cardiac surgery patients. And then we have a second question. So, when choosing sedation for cardiac surgery patients, do you think that you'll be less likely to use dexmedetomidine as a result of the DECI trial? If the answer is yes, no, or not quite sure yet. And here's the result. So, it looks like a lot of people are not very convinced by this trial because there are a few people that say that they will not be less likely to use dexmedetomidine as a result of the results of this trial, and some people are still unsure yet. So, that concludes my presentation. I just wanted to say thank you for your attention and the participation with the polling questions. I believe we have a lot of time now for questions and comments before the next presentation begins if anyone would like to add to the discussion, but thank you again. Thank you, Catherine. We do have a few questions. As a reminder, you can type your questions in the questions box. We have two similar questions. Did the authors analyze utilization of other sedatives in the immediate post-op period like propofol or benzodiazepines? And then did they report the use of non-opioid analgesics like acetaminophen? No, I did think that this was a limitation of assessing the results of the trial because they did not report in their actual published article or in the supplement that they had what they used for other sedatives or what the trends were if we had a significant portion of perhaps benzodiazepines or propofol in one group versus the other, which definitely, I believe, could have influenced the results as far as incidences of hypotension or delirium. The closest thing that they did analyze is if there were any differences across the different treatment sites to see if maybe different practices at different sites had any influence at what the results would be, but there was not noted any differences that were significant between the treatments at different sites. So, I do think that that is a significant limitation if we can really say that it was dexmedetomidine that caused these results or if perhaps there was a significant use of one arm versus the other arm that could have influenced the results of the trial. And as far as there was a question you mentioned about non-sedative agents like other analgesics such as acetaminophen, and they did not comment on that either. Okay, thank you. In the interest of time, I'm going to do the next one and then that will probably be all the time we have for questions here. How does the cardiac surgery population in this trial differ from prior positive studies of cardiac surgery patients with dexmedetomidine use? What I felt is that these patients actually really, they well reflected some of the other patients in the other trials. From what I noted, at least the baseline control arm did have similar number or similar rate of atrial fibrillation as they found in other studies because their power calculation was essentially right on with how they expected the number of patients to experience atrial fibrillation in the control arm. So I do believe that these results would be comparable or these patient populations should be comparable, but the other studies were a little bit weaker. They didn't have enough patients in the other studies potentially to detect a difference. And also some of the studies were more observational. The study that I mentioned that was prospective and included 88 patients that was a positive trial, it did have a high fragility index. There was only one patient that would have made the trial insignificant in the improvement of atrial fibrillation. So I think that that could be a potential reason we included more patients in this trial. So that is why we were able to see that there was maybe not a difference that would have been expected. Great. Thank you, Catherine. That concludes our question and answer session. I'd like to now move on and introduce our second presenter, Ashley Camp. Hello, everyone. My name is Ashley Camp, and I'm the PGY-2 Critical Care Pharmacy Resident at Duke University Hospital. Today, I'll be presenting on dexamethasone in hospitalized patients with COVID-19, a preliminary report, also known as a recovery trial. Before we dive into recovery, let's take a few steps back to discuss the pathophysiology of COVID-19 and the potential role of corticosteroids in this disease state. A three-stage classification system has been proposed for COVID-19. Stage 1, the phase of early infection, is characterized by mild and often nonspecific symptoms in the setting of viral replication. During stage 2, the pulmonary phase, symptoms may evolve to shortness of breath or hypoxia as the host inflammatory response activates. A subset of patients with severe disease may progress into stage 3, which is characterized by systemic hyperinflammation. This complex pathophysiology may make the timing of pharmacotherapy for COVID-19 of critical importance. Antiviral agents demonstrate promise in the early stages of COVID-19 when viral response is high, whereas corticosteroids given too early may actually promote viral replication. Use of corticosteroids has been proposed later in the clinical course of COVID-19 to minimize the deleterious effects of systemic hyperinflammation. However, there are many considerations when evaluating the role of corticosteroids in COVID-19. With regard to their place in therapy for viral illnesses, the majority of recent data comes from the influenza A or H1N1 pandemic of 2009. In patients with H1N1, a possible increase in mortality was reported with the use of corticosteroids in several studies. In a recent systematic review and meta-analysis published by Zhang and colleagues, use of corticosteroids in patients with H1N1 was associated with a 1.85 times greater odds of mortality in 14 case control studies. Moving our discussion into ARDS, which may be caused by numerous non-viral causes, several interesting studies with methodological limitations have been published. Most recently, the DEXA ARDS study reported an increase in the number of ventilator-free days at 28 days with a decrease in mortality at day 60 in patients with moderate to severe ARDS treated with a course of dexamethasone. One major limitation of this study was a lack of standardization with regard to usual care across centers. The role of corticosteroids for COVID-19 becomes more unclear when we consider that not only patients with this viral illness present with ARDS. Despite limited evidence supporting the use of these agents pre-recovery, corticosteroids were used early on in China. The largest previous trial was the GlucaCOVID trial, which reported a decrease in the composite outcome of death, admission to the ICU, or requirement of non-invasive mechanical ventilation in patients with COVID-19 who were treated with methylprednisolone. However, this trial has not been peer-reviewed, and therefore should be interpreted with caution. Given these numerous considerations, our three major consensus guidelines for COVID-19 prior to the publication of recovery were mixed in their recommendations. The Infectious Diseases Society of America recommended use of corticosteroids only in hospitalized patients with COVID-19 pneumonia, while the National Institutes of Health suggested use only in mechanically ventilated patients with COVID-19 without ARDS. Meanwhile, the Surviving Sepsis Campaign took the opposite stance, suggesting use in mechanically ventilated patients with both COVID-19 and ARDS. Moving into our first assessment question, at your institution, what population of hospitalized patients with COVID-19 was treated with corticosteroids before publication of the recovery trial? None, patients receiving any respiratory support, only patients receiving invasive mechanical ventilation, or all patients regardless of respiratory support. Okay, and so we see our results here, and we can see that the majority of respondents said that patients received corticosteroids if they were receiving any respiratory support, but we can see that practice was generally mixed before recovery. At our institution, I will say that we were not routinely using corticosteroids in patients with COVID-19 who were hospitalized. The conflicting considerations discussed and overall lack of data specific to the use of corticosteroids in COVID-19 were the driving forces behind the recovery trial, which was published in the New England Journal last month. This trial aimed to determine if dexamethasone could reduce 28-day mortality in hospitalized patients with COVID-19 when compared to usual care. Recovery was a multi-center, pragmatic, open-label, randomized, controlled trial that was conducted at 172 sites across the United Kingdom. Patients were enrolled between March 19th and June 8th of 2020. Eligible patients were randomized in a 2-to-1 ratio to receive usual care or treatment with either intravenous or oral dexamethasone, so 6 milligrams once daily for 10 days or until hospital discharge, whichever was sooner. Patients in both the usual care and dexamethasone groups were able to receive other investigational agents. They also had the potential to undergo further randomization to receive convalescent plasma or tocilizumab in the setting of progressive disease. Patients were included if they were at least 18 years of age and hospitalized for either clinically suspected or laboratory-confirmed SARS-CoV-2 infection. This age limit was removed starting on May 9th. Exclusion criteria were any known contraindications to dexamethasone, any medical history deemed a substantial risk by the attending clinician, or if dexamethasone was unavailable at the trial site. The primary outcome was the incidence of all-cause mortality within 28 days. Secondary outcomes included hospital length of stay, receipt of invasive mechanical ventilation or death among patients not receiving mechanical ventilation at randomization, cause-specific mortality, receipt of renal replacement therapies, and receipt and duration of mechanical ventilation. However, only the first two secondary outcomes were reported in this article. With regard to statistical analyses, a baseline mortality rate of 28% within 28 days was assumed based on previous mortality estimates in hospitalized patients with COVID-19. Based on this assumption, the authors aim to enroll 6,000 patients to provide 90% statistical power at a significance level of 0.01 and to detect a 4% absolute risk reduction and a 20% relative risk reduction in the primary outcome. This was an intention to treat analyses, and Cox regression was used to estimate mortality rate ratios, which can be interpreted similarly to risk ratios when the outcome is death. Subgroup analyses were performed based on age, sex, level of respiratory support at randomization, days since symptom onset, and predicted 28-day mortality risk. In total, 11,303 patients were recruited, and 6,425 patients underwent randomization. 2,104 patients were randomized to receive up to a 10-day course of dextromethazone, while 4,321 patients were randomized to receive usual care. This slide describes the baseline characteristics of enrolled patients. Overall, groups were well-balanced with regard to all baseline characteristics, with the exception of age. On average, patients in the dextromethazone group were 1.1 years older, which is notable because advanced age is associated with an increased mortality risk in COVID-19. Patients receiving dextromethazone were randomized a median of 8 days since symptom onset and 2 days since hospitalization. At the time of randomization, 24% of patients in the dextromethazone group did not require any respiratory support, while 61% received supplemental oxygen and 15% received invasive mechanical ventilation. It is worthwhile to mention that patients who received respiratory support at randomization presented further from symptom onset than patients who did not. Additionally, 88% of patients tested positive for SARS-CoV-2, and the median duration of dextromethazone therapy was 7 days. In evaluation of the primary outcomes, 22.9% of patients receiving dextromethazone experienced death within 28 days compared to 25.7% of patients receiving usual care. This was associated with a rate ratio of 0.83 and a statistically significant P-value. Patients in the dextromethazone group were also discharged from the hospital a median of 1 day sooner than patients in the usual care group. 67.2% of patients receiving dextromethazone were discharged from the hospital within 28 days compared to 63.5% of patients receiving usual care. Additionally, among patients not receiving invasive mechanical ventilation at randomization, dextromethazone use was associated with a statistically significant reduction in the risk for requirement of invasive mechanical ventilation. However, a statistically significant difference was not observed in the composite outcome of death or requirement of invasive mechanical ventilation. In subgroup analyses of the primary outcome, we can see that the observed reduction in mortality within 28 days was driven by the subgroup of patients receiving respiratory support at randomization in the form of invasive mechanical ventilation or supplemental oxygen. However, no benefit in the possibility of harm was observed among patients who did not require supplemental oxygen at randomization. Dextromethazone was also favored in the subgroup of patients randomized more than 7 days after symptom onset. However, it is important to note that a greater proportion of these patients also received respiratory support at randomization. No difference with regard to age, sex, or predicted 28-day mortality risk were identified. Based on these results, the authors concluded that among hospitalized patients with COVID-19 receiving respiratory support in the form of invasive mechanical ventilation or supplemental oxygen at randomization, dextromethazone use demonstrated a benefit with regard to all-cause mortality within 28 days when compared to usual care. However, no mortality benefit in the possibility of harm was observed in patients not receiving supplemental oxygen at randomization. Overall, recovery was a well-designed trial that met its pre-specified enrollment goals to achieve statistical power. Additionally, the primary outcome was appropriate based on the previously reported average time to death of 22 days for hospitalized patients with COVID-19. The trial also had an excellent follow-up rate of 99%. However, recovery was limited by its open-label design and its 8% rate of crossover from the control-to-treatment group. Additionally, there was heterogeneity in the timing of inclusion as patients were randomized between 1 and 5 days of hospitalization. There was also a notable risk for selection bias. The usual care interventions, including those associated with reduced mortality and the amount of oxygen required at randomization, were poorly described. The trial's conclusion was also based on a subgroup of analyses. Finally, adverse events were not reported in this study, so the safety of dexamethasone in hospitalized patients with COVID-19 remains unclear. For our second polling question, has the recovery trial changed practice at your institution with regard to the use of corticosteroids in hospitalized patients with COVID-19? No, never use steroids. No, and I always use them. Yes, now use corticosteroids in all hospitalized patients with COVID-19. Or, yes, I now use corticosteroids in hospitalized COVID-19 patients requiring respiratory support. Perfect. And this is what we expected. This really was a game-changing trial. As you can see, the majority of respondents said that, yes, the recovery trial changed practice, and they're now using corticosteroids in patients who require respiratory support. As I mentioned, the publication of recovery resulted in substantial changes, both in practice, which were reflected in our consensus guidelines. Currently, the National Institutes of Health suggest the use of dexamethasone in mechanically ventilated patients or those requiring supplemental oxygen. The Infectious Diseases Society of America suggests the use of dexamethasone for up to 10 days in our hospitalized patients with severe COVID-19 in accordance with the results of this trial. In conclusion, recovery is the largest and only peer-reviewed multicenter randomized control trial to date to evaluate the use of corticosteroids, specifically dexamethasone, in hospitalized patients with COVID-19. I believe dexamethasone's place in therapy aligns well with our updated consensus guideline recommendation that suggests its use in hospitalized patients with severe COVID-19 who require invasive mechanical ventilation or supplemental oxygen. Recovery also has four ongoing evaluations, including the dexamethasone arm, which is now only recruiting children, so be on the lookout for additional publications in the coming months. Thank you so much for your time and for allowing me the opportunity to present on recovery. I'd be more than happy to answer any questions from the audience at this time. Thank you, Ashley. Our first question is, what can you conclude about dexamethasone dose utilized in recovery compared to equivalent doses of corticosteroids for other critical illnesses? Yeah, so that's a really good question. So a dose of dexamethasone, 6 milligrams a day, is equivalent to about 160 milligrams of hydrocortisone. However, we do have increased glucocorticoid activity with dexamethasone, so similar to some doses of corticosteroids used in other critical illnesses. I believe dexamethasone was chosen for this trial, though, given its ability to be given both intravenously and by mouth in its long half-life, which favors once-daily dosing. Great, thank you. What are your thoughts on the use of steroids in the upcoming flu season if a patient tests positive for both flu and also COVID? Yeah, and honestly, that's a really good question. The recovery trial, I mean, very well-designed during this pandemic, but I think we do have some important considerations. So we do have previous data with use in specifically H1N1, but for patients, honestly, I might be hesitant, especially if these patients are, say, not receiving invasive mechanical ventilation at baseline. So it's definitely something to consider, and I would probably only use dexamethasone in our patients with progressive severe disease who otherwise do not have a contraindication to use. Great, thank you. And then we probably have time for one more question here. Anecdotally, do you think universal use of dexamethasone in patients requiring respiratory support has improved outcomes in patients with COVID at your institution? I will say this has resulted in drastic practice changes at our institution. I have not taken care of a robust number of COVID patients, but I will say empirically, I have had relatively good luck with using dexamethasone in our patients requiring respiratory support at baseline. Great, thanks. That concludes our Q&A for this session. Thank you, Ashley. I'd now like to introduce our final presenter, David Ragunanan. Thank you very much for that introduction. My name is David Ragunanan, and I'm the PGY-2 Critical Care Pharmacy resident here at Tampa General, and today we'll be discussing the outcomes of metabolic resuscitation using ascorbic acid, thiamine, and glucocorticoids in the early treatment of sepsis, also known as the Orange's Trial, published in the Chest Journal. At this time, I'd like to state I have nothing to disclose regarding any of the contents of this presentation. And for our first polling question, does your organization utilize hydrocortisone, ascorbic acid, and thiamine, or HAP, combination therapy in patients with septic shock? And it looks like the majority of institutions do not currently use this combination therapy, and it's a valid answer because there is a lot of controversy regarding the utilization of this combination therapy. And hopefully at the end of this presentation, we can add some clarity to that and see some differing results at the next poll. So to truly understand the importance of the Orange's Trial, let's take a look at some of the studies that utilize the HAP combination therapy. So in 2017, American colleagues conducted a retrospective before-after study comparing the utilization of HAP combination therapy, defined as hydrocortisone 50 milligrams every 6 hours, ascorbic acid 1.5 grams every 6 hours, and thiamine 200 milligrams every 12 hours to the standard of care. What they found was significant reductions in vasopressor duration, hospital mortality, and the risk of acute kidney injury and SOPA score. In 2019, Fowler and colleagues conducted the Citrus Ali trial, which was a randomized multicenter double-blind placebo-controlled trial that looked at patients that had both ARDS and septic shock. They compared patients that received ascorbic acid at 50 milligrams per kilogram every 6 hours, which was a much higher dose when compared to the study by American colleagues. And they compared this to control group, which was a matching placebo. They did not find a significant difference in their primary outcome, which was the change in SOPA score. But however, they found significant improvements in 28-day mortality and significant improvements in ICU and hospital-free days. Earlier this year, Fuji and colleagues conducted the Vitamins trial, and this was a multicenter open-label randomized controlled trial comparing the utilization of HAP therapy, defined as hydrocortisone 50 milligrams every 6 hours, ascorbic acid 1.5 grams every 6 hours, and thiamine 200 milligrams every 12 hours, very similarly to what was done in the study by American colleagues. And they compared this to a control group, which was hydrocortisone 50 milligrams every 6 hours, based on the efficacy of hydrocortisone and septic toxin in the adrenal and approach trials in 2018. They found no significant difference in the time alive or free of vasopressors, and there was no significant differences among secondary outcomes. Some of the reasons why these studies may have had conflicting findings are the time to intervention, the hydrocortisone administration in the control group, and the differences in the study population. When we look at the time to drug administration after enrollment, this was 6 hours in the Citrus Ali study and 12 hours in the Vitamins trial. But when we look at enrollment, enrollment occurred in the Citrus Ali study up to 48 hours after the diagnosis of septic shock, and in the Vitamins trial, enrollment occurred up to 24 hours after onset of shock. The current guidelines recommend sepsis bundle to be initiated within the first hour, so as you can see, this delay was actually about 36 to 54 hours to intervention of the HAPS therapy group. The change in the SOFA score was significantly improved in the Vitamins trial at 72 hours, but there was no significant difference when looking at the Citrus Ali study at 96 hours. More importantly, when we evaluate the utilization of corticosteroids given in the control group, looking back at the study by American colleagues in 2017, 59.6% of patients in the control group received corticosteroids. In the Citrus Ali study, 65% of the patients in the control group received corticosteroids, and in the Vitamins trial, 100% of these patients received corticosteroids. So a lot of experts believe that the mortality benefits seen in the study by American colleagues was mainly driven by a large proportion of patients in the control group not receiving corticosteroids. Most recently this year, a study by Long and colleagues, this was a retrospective cohort of 206 patients where 79 of these patients received hydrocortisone, 50 milligrams every six hours, ascorbic acid, 1.5 grams every six hours, and thiamine, 200 milligrams every 12 hours. And they found that the ICU mortality ratio, it actually increased linearly with any delays in the treatment from the initial sepsis presentation. So when we look at this figure, the orange columns represented the expected ICU mortality, whereas the blue columns represented the observed ICU mortality. And what they found in this retrospective cohort is when this hot therapy was initiated within the first six hours of sepsis presentation, these patients had a 0% observed ICU mortality where it was actually expected to be closer to 18.7%. So although this is a retrospective study, it is important to note that they show a significant benefit when adding on hot therapy earlier in sepsis. There are multiple effects of hydrocortisone, vitamin C, and thiamine in the setting of sepsis. Vitamin C and thiamine, they act as antioxidants for free radicals and inhibit activation of xanthine oxidase and NADP oxidase. Also vitamin C protects the mitochondria from oxidative stress and the thiamine increases the activity of pyruvate dehydrogenase, thereby increasing ATP. Vitamin C and hydrocortisone, they restore the endothelial tight junctions and they increase the adrenergic receptor function. And finally, the vitamin C and the hydrocortisone combo, they also prevent the loosening of the tight junctions of the endothelium. This decreases vascular permeability in patients that are progressing into septic shock. The authors of the Orange's trial, they wanted to answer the question, does hydrocortisone, ascorbic acid, thiamine, or HAP combination therapy improve clinical outcomes in sepsis and septic shock? This was a randomized double-blind placebo-controlled trial conducted at two community non-teaching hospitals in the United States. The intervention group, which contained 68 patients, they received ascorbic acid 1.5 grams every six hours for four days, thiamine 200 milligrams every 12 hours for four days, and hydrocortisone 50 milligrams every six hours for four days. This was compared to the control group, which was a placebo. However, patients in the placebo group, they were allowed to receive corticosteroids based on the discretion of the provider. It was estimated that 94 subjects would be required for 80% power. The primary analysis was done with an intention to treat, and they utilized Kaplan-Meier curves to assess the primary outcome. In addition, a one-way analysis of covariance, or ANCOVA, was utilized to adjust for corticosteroid use as a covariate. The authors included patients who were 18 years and older with a diagnosis of sepsis or septic shock within 12 hours of ICU admission. However, they excluded patients if they had sepsis or septic shock for more than 24 hours from admission, if they were transferred from another hospital, or if they had a terminal end-stage disease. The primary outcomes were time to vasopressor discontinuation in hours and the change in SOFA score. Some of the secondary outcomes include 28-day mortality, procalcitonin clearance at 96 hours, and ICU mortality. They found no significant difference in any of the baseline characteristics between the groups. However, it is important to note that a total of 41% of patients in the comparator group received corticosteroids. When we look at the primary outcome, there was a significant reduction in time to vasopressor discontinuation in hours, with 27 hours seen in the intervention group compared to 53 hours in the placebo group. And this was statistically significant. In order to assess for the corticosteroid effect, they conducted that nonparametric rank ANCOVA, and it showed that hat combination therapy remained significant for the primary outcome. Of note, they found no significant change in SOFA score between groups of 72 hours. And looking at the secondary outcomes, there was no significant differences in any of the secondary outcomes. But when we look at ICU mortality and hospital mortality, this was numerically lower in the hat group. However, the study was underpowered to detect a significant difference. When we look at the SOFA score and the procalcitonin clearance, this actually may have been affected due to the less severity of ascorbic acid hypovitaminosis that was seen in this study when compared to previous studies. The median ascorbic acid level at baseline was 21.7 micromoles per liter in this study compared to 14.7 micromoles per liter in the study by American colleagues. The authors concluded that hat combination therapy is safe, and it does decrease the duration of shock in patients with sepsis, and it appears to be due to the ascorbic acid component. They also state that further randomized trials were needed in order to assess its efficacy in terms of mortality and ICU length of stay. Some of the strengths of the study included its nonparametric ANCOVA to account for steroid use. So what this really means is the authors and investigators, they divided these patients into three separate groups. The first group included patients that received hydrocortisone, ascorbic acid, and thiamine. Second group included patients that just received hydrocortisone. And the third group was patients that just received placebo. And they assessed these three different groups for the primary outcome and still found a significant reduction in time to vasopressor discontinuation in patients that received ascorbic acid, hydrocortisone, and thiamine. This led to the hypothesis that ascorbic acid has an independent hemodynamic benefit in comparison to hydrocortisone alone. Secondly, patients were randomized within 12 hours of ICU admission, which is much sooner than any of the previous studies with the exception of the study by American colleagues. They also had consistent dosing for haptherapy using the same dosing that was used in both the vitamins trial and the study by American colleagues. Some of the limitations of the study, however, is the homogenous population, which was primarily white, the relatively small sample size, which was unable to detect any significant differences in the secondary outcomes. And also the primary outcome was changed after the completion of data collection. So initially this study, the primary outcome was ICU mortality. And after data collection was completed, the authors changed the primary outcome to time to vasopressor discontinuation. This however does weaken the study results, especially since the primary outcome was the only significant finding in this study. For our second polling question, so would the results of the ORANGES trial change how you utilize HAT combination therapy for patients in the early stages of septic shock? No. So, and this means most of the institutions, this study really, it can't really change a lot of the practices that we're seeing and a lot of the reasons why we should be using hat combination therapy. And really, this brings us to where we are right now in terms of septic shock treatment, knowing that septic shock has this increased mortality in patients. And there's a lot of controversy still revolving around the utilization of hat combination therapy. Based on the findings of this study, hat therapy may have a role in select patients. It's interesting based on that retrospective study that they saw most benefit within the first six hours of sepsis. But previously, or future directions, the vitamin C, thiamine, and steroids in sepsis, the VICTIS trial, just completed its enrollment, looking at 501 patients. And they actually randomized patients in a one-to-one fashion to receive either hat therapy or matching placebo. And they randomized these patients within 24 hours. So, the authors and investigators of that randomized cohort from earlier this year, they wrote to the authors of the VICTIS trial, suggesting that a subgroup analysis be done to evaluate the relationship between the timing and the clinical outcomes in these patients with septic shock. And it would be very interesting to see if the VICTIS trial is able to duplicate the findings seen in that retrospective study, where earlier hat therapy may have a role and may have a benefit in patients with septic shock. In summary, hat therapy is safe and appears to be the most beneficial during the first six hours of septic shock. Findings of the study suggest that the ascorbic acid has a hemodynamic benefit, which is independent of steroids and septic shock. And ongoing studies may provide clarity on whether or not hat combination therapy has an effect on mortality or ICU length of stay. At this time, I'd like to state thank you for your time, your attention, and the opportunity for me to discuss this trial with you. I'd like to open up the floor for any possible questions. Great. Thank you, David. We do have a couple questions. How did they account for patients who died when analyzing the outcome of resolution of shock? And how do you think this had an impact on the primary endpoint? So when they looked at the outcome of time to vasopressor discontinuation, they defined that as the resolution of shock. And when accounting for if a patient died before the resolution of shock, they were not included in the analysis for time to vasopressor discontinuation. So those patients were excluded for the primary analysis. Okay. Thank you. The next question is, is there any patient population that you still see use of vitamin C as a viable option? And then how do you use hat therapy at your institution? Thank you. That's a good question. So I do think that there is a role for combination hat therapy with ascorbic acid in patients that are in sepsis but are progressing towards sepsis shock. I do believe that there is a point where it becomes too late to add on hat combination therapy. And at that point, it may not have any benefit at all. At our institution, we use hat combination therapy based on the discretion of the provider. I do believe that it is time sensitive. And I do think that that needs to be proven in studies. However, when we look at some of the studies that's been done, most of these studies have randomized and enrolled these patients 24 to 36 hours after their ICU admission, and sometimes 12 to 16 hours after the actual diagnosis of septic shock. And so I believe in that patient population, it may actually be too late. And three days ago, the ACT trial actually showed no significant difference in SOFA score or ICU mortality, but they had a numerical increase in mortality in those patients. And they actually were randomized more than 24 hours after the onset of shock. So the theory then becomes, is there too late of a period of time that we are adding on hat combination therapy? And that has not been proven, but I do think that there is a role if we add it on early enough to decrease that cytokine score. Great. Thank you. One more question. What are your thoughts on the use of high dose vitamin C in patients with acute renal failure or those requiring continuous renal replacement therapy? So based on the, if we're using hat combination therapy, most of the dosing that's recommended would not be the high dose continuous vitamin C infusions, unless we're looking at the study that was done, the Citrus Ali study where they use 50 milligrams per kilogram. In that population, I looked into it. They did have some, it was not statistically significant, but there was a trend toward increase in AKI. I do think that that is a concern. However, in this specific study, they did not mention whether or not the ascorbic acid at that lower dose of 1.5 grams has any effect on renal function. So it does seem safe at the lower dose. Great. Thanks. And one final question. Given that the primary endpoint of resolution of shock and that only 75% of patients at baseline were on vasopressors, how do you think more patients in the placebo group starting pressors after enrollment impacted the primary endpoint? I mean, definitely if more, if more patients in the placebo group are starting vasopressors after enrollment, then their time to discontinuation of vasopressors may in turn be longer than patients that are starting vasopressors before, you know, when you're looking at it in terms of time to vasopressors discontinuation. So this is a great question. And I do think it does skew the results some. I do think that patients, the study itself, the way it is designed that the patients in the intervention group, it's possible to say that that could have been the reason why we see such a drastic decrease in terms of timeframe for vasopressor discontinuation. However, I do not think that it is the determining factor. I do think that hat therapy does have a role in terms of hemodynamic stability. And I, but it is a great question and a great point. That is an additional weakness in the study. Yes. Wonderful. Thank you. Well, I'd like to thank all of our presenters today in the audience for attending. Please join us on the third Friday of the month from 2 to 3 PM Eastern Standard Time for the next Journal Club Spotlight on Pharmacy. That concludes our presentation today. Thank you. Thank you, Megan. Thank you for having me.

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