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 Nhi M. Mello, Clinical Pharmacy Specialist in Trauma Surgical ICU at Truman Medical Centers in Kansas City, Missouri. 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 Q&A after each of today's speakers. To submit questions throughout the presentation, type into the question box located on your control panel. You will also have the opportunity to participate in several interactive polls. When you see a poll, simply click the bubble next to your choice. 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 opinions or views of SCCM. SCCM does not recommend or endorse any specific test, position, product, procedure, opinion, or other information that may be monitored. And now I'd like to introduce your speakers for today. Each will give a 15-minute presentation followed by a Q&A. Our first presenter today is Colton Rath, PGY-2 critical care resident at University of Utah Health in Salt Lake City, Utah. Our second presenter is Brooke Barlow, PGY-2 critical care resident at University of Kentucky Health Care in Lexington, Kentucky. And our third presenter is Callie Curran, PGY-2 critical care resident at Beth Israel Deaconess Medical Center in Boston, Massachusetts. And now I'll turn things over to our first presenter. Good afternoon, everyone. My name is Colton Rathberg, and the title of my presentation today is Continuing the Chat on HAT, where we are going to be discussing the latest hydrocortisone, ascorbic acid, and thiamin therapy study, the VICTIS trial. So, moving forward throughout this presentation, I will refer to the hydrocortisone, ascorbic acid, and thiamin therapy as HAT therapy. So, the objectives of today's presentation are to review the proposed mechanism of action of HAT therapy in sepsis and septic shock, review the previously published literature involving HAT therapy, and last, evaluate the clinical significance of the VICTIS trial on clinical practice. And so, before we dig into the VICTIS trial, we will briefly review the Surviving Sepsis Campaign guideline recommendations and previously published literature surrounding the controversial addition of HAT therapy to treat patients with sepsis and septic shock. And so, currently, the Surviving Sepsis Campaign provides a weak recommendation for the initiation of hydrocortisone to treat septic shock when adequate fluid resuscitation and vasopressor therapy are unable to restore hemodynamic stability. And so, the Surviving Sepsis Campaign makes no recommendation regarding the initiation of HAT therapy. So, the controversial addition of HAT therapy began in 2017 when Merrick and colleagues published a small, single-center, retrospective study that compared HAT therapy to placebo in patients with severe sepsis or septic shock. Specifically, they utilized a combination regimen of hydrocortisone, 50 mg IV every 6 hours, ascorbic acid, 1.5 g IV every 6 hours, and thiamine, 200 mg IV every 12 hours. So, Merrick and colleagues ultimately found a statistically significant reduction in hospital mortality with a number needed to treat up to 3 and a statistically significant reduction in the duration of vasopressor use. And so, the mortality benefit seen in the study has resulted in numerous trials being published in the past year regarding HAT use in sepsis. And so, to understand how HAT therapy may be of benefit in sepsis, we must first identify how each aspect of HAT therapy works to counteract sepsis. And so, starting with hydrocortisone, published data has suggested that critical illness induces a state of absolute or relative adrenal insufficiency that may contribute to shock. And it is believed that the administration of corticosteroids in sepsis may help to restore balance to the altered HPA axis. And so, published literature regarding the use of hydrocortisone in septic shock has consistently found that the addition of steroids results in a more rapid time-to-shock resolution but has yet to demonstrate a consistent mortality benefit. So, ascorbic acid is a water-soluble vitamin that acts as an electron donor that directly scavenges and prevents the generation of new free radicals. Data has shown that plasma and cellular levels of ascorbic acid rapidly decline during critical illness, suggesting that repletion may be necessary in sepsis and septic shock. Ascorbic acid is essential in the generation of endogenous vasopressors and ophelial regulation and may enhance glucocorticoid binding to glucocorticoid receptors by reducing free radicals. And so, the rapid drop of ascorbic acid levels in critical illness may contribute to vascular dysfunction and impair glucocorticoid activity. And so, thiamine is also a water-soluble vitamin that specifically acts as a cofactor for pyruvate dehydrogenase, the enzyme necessary for converting pyruvate to acetyl coenzyme A for entry into the citric acid cycle. When thiamine levels are insufficient, pyruvate is unable to enter the citric acid cycle, which results in impaired aerobic respiration and a shift to anaerobic metabolic pathways that ends with lactate accumulation. And so, coupled with hydrocortisone and ascorbic acid, thiamine supplementation during critical illness may reduce lactate accumulation and prevent organ dysfunction. And so, as mentioned previously, the mortality benefits seen by Merrick and colleagues have prompted numerous subsequent trials that need to be reviewed briefly before discussing the VICTIS trial. And so, first, we will look at the trial by Fuji and colleagues that was published in January of 2020. They conducted a prospective multi-center study that compared HAT therapy to hydrocortisone monotherapy in patients with septic shock. Ultimately, the authors found that HAT therapy resulted in no statistically significant difference in time alive or vasopressor-free days when compared to hydrocortisone monotherapy. Additionally, they also found that HAT therapy resulted in no 28-day, 90-day, or ICU mortality, which directly contradicts the results found by Merrick and colleagues. So, then in March of 2020, Iglesias and colleagues, they published a prospective study that evaluated HAT therapy in sepsis and septic shock. In this prospective trial, the authors ultimately found a statistically significant reduction in time-to-shock resolution with a 26-hour time difference. But despite a more rapid time-to-shock resolution, the authors did not find a statistically significant reduction in ICU or hospital mortality, which also directly contradicts the results found by Merrick and colleagues. So, also in March of 2020, Chang and colleagues published a first prospective study that evaluated the effect of HAT therapy on mortality. And unfortunately, this trial was terminated early due to the high incidence of severe hypernatremia and suspected ineffectiveness of HAT therapy, which likely resulted in the final analysis being underpowered to detect a true difference. So, in the end, Chang and colleagues found no statistically significant difference in 28-day mortality, ICU length of stay, or duration of vasopressor use. However, they did find a statistically significant increase in the incidence of severe hypernatremia. Next, we'll be looking at a study published by Moskowitz and colleagues in August of 2020. They conducted a prospective trial that sought to determine if the initiation of HAT therapy resulted in a change in SOFA scores at 72 hours, and if HAT therapy increased the incidence of renal failure compared to control. Of note, this trial specifically utilized a thiamine dosing strategy of 100 mg Q6 hours instead of the 200 mg Q12 hours, unlike previously published trials. So, the authors ultimately found that there was no statistically significant difference in 72-hour SOFA scores, the incidence of renal failure, or 30-day mortality. And last, Mohamed and colleagues, in September of 2020, they published a prospective trial that sought to evaluate the use of HAT therapy on hospital mortality. This trial directly contradicts the results found by Merrick and colleagues, as there was no noted statistically significant difference in hospital mortality. They did, however, note a statistically significant reduction in time-to-shock reversal, but did not note a reduction in ICU-length stay. And so, following the review of the six published trials regarding the use of HAT therapy in septic shock, there are still many questions that must be answered. Specifically, does HAT therapy result in a reduction in ventilator days, vasopressor days, and mortality? And so, the VICTIS trial attempts to answer some of these questions here. And so, now that we have reviewed the mechanism of action of HAT therapy in sepsis and discussed previously published literature, it is time to specifically discuss the VICTIS trial. So, the purpose of the VICTIS trial was to determine if HAT therapy increased ventilator and decreased ventilator and vasopressor free days in comparison to placebo alone. The VICTIS trial is the largest published trial to date comparing HAT therapy to placebo in patients with sepsis. Additionally, the VICTIS trial is the first study that sought to assess the effect of HAT therapy on ventilator and vasopressor free days, which is a clinically relevant outcome in our septic patients. Because, as we know, previously published literature has shown us that prolonged courses in mechanical ventilation and longer durations of vasopressor use result in worse outcomes for our critically ill patients. So, this trial was a multicenter, randomized, double-blind, placebo-controlled trial that specifically looked at patients with sepsis-induced respiratory and or cardiovascular dysfunction. And their intervention was HAT therapy versus placebo. And per the trial protocol, first doses must be administered as soon as possible, ideally within four hours, but no longer than six hours from randomization. And it is important to note also that participants could be treated with open-label corticosteroids at the discretion of the clinical team. So, to be included in this trial, patients had to have a suspected or confirmed infection. They had to have a confirmed or planned ICU admission. And most importantly, they had to have acute respiratory failure or acute cardiovascular dysfunction due to sepsis. And so, patients were excluded from this trial if they were less than 18 years of age. Their organ dysfunction was no longer present at the time of randomization. If they had another cause of respiratory or cardiovascular failure, including chronic hypoxemia and chronic cardiovascular failure, they were also excluded if their life expected lifespan was less than 30 days. And so, this is not an all-inclusive list of the exclusion criteria. But the authors attempted to exclude patients with other causes of respiratory or cardiovascular failure or those who may not survive long enough for evaluation of the primary outcome. So, the primary outcome of the VICTIS trial, they were looking at the difference in ventilator and vasopressor-free days in the first 30 days following randomization to receive hat therapy or placebo. Secondary outcomes of the VICTIS trial aligned with outcomes published previously in other hat therapy trials. Specifically, they sought to assess three separate mortality measures in addition to the length of ICU and hospital length of stay. The VICTIS trial also assessed kidney replacement-free days to determine if hat therapy was able to prevent the development of additional end-organ damage. And last, the evaluation of coma-slash-delirium-free days with hat therapy has yet to be assessed by any other trial that I'm aware of. And so, this trial was designed to detect a difference of 1.5 ventilator and vasopressor-free days. The primary outcome was compared using a Wilcomson rank-sum test. And then, mortality endpoints were compared using a chi-squared test in the Cox Proportional Hazard Model. And so, now, looking at the results of the VICTIS trial, of note, we do need to look at open-label steroids. So, open-label steroids were administered to 33% of patients in the hat group and 32% of patients in the placebo group. So, now, specifically looking at ventilator and vasopressor-free days, hat therapy actually resulted in less ventilator and vasopressor-free days in comparison to placebo, but there was no statistically significant difference reported between the groups. Now, looking at patient mortality, the addition of hat therapy did not result in a statistically significant difference in any mortality measure. So, 30-day mortality was 22% compared to 24% with a number needed to treat 50. 180-day mortality was actually higher in patients who received hat therapy with that number needed to harm of 37. And then, last, ICU mortality was similar between the two groups, 16.6% versus 17% with a number needed to treat of 250. There was no difference in ICU length of stay, but hat therapy actually increased hospital length of stay by one day without statistical significance. And last, there was no statistically significant difference in kidney replacement-free days and coma or delirium-free days. And so, the authors ultimately concluded that hat therapy did not significantly increase the ventilator and vasopressor-free days when compared to placebo. There were two unusual circumstances that set this hat therapy trial apart from any previously published article. The first was that the trial was terminated early due to a change in the funder's priorities, which resulted in the funding being withheld. And second, an author of the trial served as a chair of the Data and Safety Monitoring Board for this trial. So, some strengths of this trial. They planned for early administration of hat therapy, looking at 4 hours within trial randomization. And individuals were enrolled in this trial within 24 hours of the development of STEP-CIFS. They were looking at a clinically relevant primary outcome. Some key limitations of this trial is the fact that it was terminated early due to funding withdrawal. So, necessarily, we may not have been able to enroll enough patients to see a true difference in the number of ventilator and vasopressor-free days. Having that author serve on the DSMB board, there could have been some sort of bias towards this trial of some sort. And then looking at open-label steroid use, the addition of steroids in the placebo group could have made it harder to detect a true difference between placebo and hat therapy. And then last, the prolonged time to hat administration. While they were planning for early administration, the mean time to administration was actually 14.7 hours. And so, my conclusions. Following the review of the previously published literature and the VICTIS trial, I believe there is insufficient data to support the routine use of hat therapy in sepsis and septic shock, given the lack of supporting evidence outside of small single-center studies. And while the VICTIS trial sought to answer a clinically relevant outcome, the early termination of the trial left a lot to be desired, and additional studies are needed before hat therapy can really become a standard of care. And so, questions that I still have remaining, is early hat administration better, perhaps starting hat therapy in the emergency room? Is that where the true mortality benefit is seen? Is there really a difference in the number of ventilator and vasopressor-free days, but it just wasn't detected in this trial? And last, does hat therapy really have a mortality benefit in sepsis and septic shock? And so, now I have two audience response questions. My first question here is, how often do you recommend hat therapy in patients with septic shock? Do you never recommend? Rarely recommend? Frequently recommend? Consistently recommend? Or for every single patient you recommend? So, it looks like we have a vast majority of our audience never recommending hat therapy for patients in septic shock. And then my last question for the audience, when do you consider initiating hat therapy in patients with septic shock, for those of you that do recommend hat therapy? With the first vasopressor, second vasopressor, third vasopressor, and when your vasopressors hit a certain dose, or again, you don't recommend hat therapy. So, we've got a couple of people with the second vasopressor, a couple with the third, and then again, most people not recommending hat therapy. And that is the end of my presentation. Thank you, everyone, for listening. I will now field any questions that anyone has. Thank you, Dr. Radford. We do have a couple questions from the audience. Looks like the first question is, Longin colleagues sent a correspondence to the authors of the VICTIS trial to look at the effect of time to intervention on clinical outcomes. What are your thoughts on this? So, specifically, this correspondence, I actually did not see someone able to comment on this. That's something that I would have to look at, and I apologize. I'm not able to speak on that correspondence. Okay. The second question is, do we really need more trials on this subject? How many negative randomized control trials have been published to date? Yeah, I was kind of thinking that as well. Yeah, I was kind of thinking that as well. In regards to further trials going forward, I know there's a couple in process right now. I think it's really just kind of going back to looking and trying to see, is there really a mortality benefit when done prospectively? The one trial that I would really like to see is initiating hat therapy in the emergency department as soon as these individuals are identified as being septic or having septic shock. For me, that's really the last kind of frontier looking at, is there really a benefit in hat therapy? But I kind of agree with this person asking this question as well. I don't necessarily know if we need any more trials to prove that hat therapy may not be beneficial. All right. And it looks like our next question is, what are your thoughts on the dose of vitamin C used in this study? So, looking at this specific dose, I know there's some other data out there. I believe it's the Citrus X, Citrus RU trial. They were looking at a very high dose of ascorbic acid, like 50 grams per kilogram, I believe is what it was. For me personally, I'm 100 kilos, so I would be getting almost 50 grams of vitamin C. I don't necessarily know if that would make a difference for me personally, but when we were looking at the PK of ascorbic acid, the 1.5 grams Q6 hours, when I was looking at it, I personally think that would be an appropriate dose. But then again, that's another question out there still is, what is the appropriate dose of vitamin C? Like for myself, I said it would be almost 50 grams a day, but I honestly don't know if that would be more beneficial over the 1.5 Q6 in my case. All right. And our last question before we move on is, was there a stated reason why funding was revoked? In the trial it was specifically looking at, it just said it was a change in the funder's priorities. As far as I'm aware, when reading this trial, the funder had, they didn't really know what was going on with the trial. They just decided, oh, I no longer want to fund this trial due to a change in my priorities, and that's essentially all that I found. And so I don't believe it was due to any negative outcomes from the trial or anything. All right. It looks like Dr. Patel has made a comment about the randomized controlled trial answer that you gave. So the comment is, a test 2020 was able to administer within one hour of randomization, although this is a small study, no difference was found. And that will conclude our Q&A session. So thank you, Colton Radford. Yeah, thank you. Before moving on to our next presenter, we would like to ask a brief polling question regarding today's attendance to gain a better understanding of our overall attendance to ensure continued support of this Spotlight on Pharmacy webcast. So how many attendees are you viewing this webinar with? Please select just one answer. So either just me, 2 to 5 people, 5 to 10 people, or greater than 10 people. And now I'd like to introduce our second presenter, Brooke Barlow. Hello and good afternoon. Thank you so much for joining today. So my presentation will be on the effect of high-dose baclofen on agitation-related events among patients with unhealthy alcohol use receiving mechanical ventilation in the intensive care unit. This was a randomized clinical trial published in JAMA of February 2021. So I'd first like to get started with a polling question and ask the audience, do you currently use any pharmacotherapy agents for the prevention of alcohol withdrawal in your current clinical practice setting? Yes or no. It seems like there's a pretty equal split here, so very interesting. I'm curious to see how this study kind of changes people's practice. So to provide a brief background about alcohol use disorder in the intensive care unit, there is a high incidence of alcohol use disorder within our population, and up to 33% of patients admitted to the intensive care unit will experience alcohol withdrawal manifestations. Now, regardless of their indication for ICU admission, these patients are at higher risk for complications, such as increased risk for infection, prolonged length of hospital and ICU stay, time on mechanical ventilation, as well as increased mortality. While there are a multitude of manifestations of alcohol withdrawal syndrome, agitation is one of the most prominent, and we do know that in the intensive care unit, patients do suffer from various different causes of agitation in the ICU. And alcohol or illicit substance use withdrawal has been identified as a leading cause of agitation in the intensive care unit. However, the management of this patient population can be very complex, and oftentimes they do require multimodal pharmacotherapy. Now, notably in the guidelines, I do want to emphasize that a treatment-based approach of symptoms of that patient's manifest of alcohol withdrawal is recommended over preventative strategies, especially in the intensive care unit. Now, discussing some of the different management strategies for alcohol withdrawal in the ICU, we do suffer some different challenges that are unique to patients that are under mechanical ventilation. So, as we know, the CWOA is a typical assessment scoring system to assess for alcohol withdrawal manifestations, but it does lack validation in patients on mechanical ventilation, which therefore warrants use of different scoring systems that are nonspecific to alcohol withdrawal, like the Richmond agitation and sedation scale. Furthermore, we do know that benzodiazepines are utilized first line for alcohol withdrawal-related manifestations. However, they're not utilized first line for continuous infusion sedation strategies for patients who are on mechanical ventilation. And patients in the ICU may warrant higher doses of benzodiazepines for their alcohol withdrawal-related manifestations, which is associated with an increased rate of adverse effects. Now, some of the normal sedative agents we may utilize in the intensive care unit, like propofol and dexmedetomidine, have been studied for alcohol withdrawal, but they're very small, mainly retrospective studies. And we do know that some of the higher doses of agents, like propofol, which patients may require for alcohol withdrawal manifestations, can lead to an increased rate of cardiovascular hemodynamic adverse effects. Furthermore, agents like Presidex only treat some of the autonomic manifestations and not specifically the GABA-mediated activity of alcohol withdrawal. And other agents, like ketamine, have limited data and only studied in the setting of refractory alcohol withdrawal. Now, overall, the evidence for preventative strategies in the ICU are limited, mainly to agents like prophylactic benzodiazepines, and the data overall is inconclusive. So this kind of leads us to thinking about other agents, maybe oral options, that can be utilized in the intensive care unit for mitigation of alcohol withdrawal-related symptoms. So this brings us to the use of baclofen. Baclofen is a GABA-B receptor agonist, which is unique compared to benzodiazepines, which work on the GABA-A receptor. Baclofen is actually FDA-approved for alcohol use disorder in France, and this is mainly due to its proposed efficacy in the outpatient setting for improving alcohol abstinence. However, in the inpatient setting, it's been less studied. Specifically, no studies have been conducted in the intensive care unit, but one study of more patients did show that it can help reduce overall benzodiazepine exposure. The dosing for patients with alcohol use disorder has ranged anywhere from 30 to 300 milligrams per day, which, as we are aware, that may exceed some of the FDA-approved labeling doses in the United States, which is 80 milligrams per day. But these patients have been seen to require higher doses of baclofen. Overall, the adverse effects of baclofen, mainly related to sedation in patients that do have higher doses of baclofen, but a benefit in this patient population is that it does not require any hepatic dose adjustments, but does require renal dose adjustments. So this brings us to the study question that the authors of the JAMA publication were looking to investigate. So they were looking to see, among critically ill patients with unhealthy alcohol use who are receiving mechanical ventilation, is high-dose baclofen effective in preventing agitation-related events in this population? The study design, this was a multicenter, double-blind, randomized, placebo-controlled trial conducted in 18 different centers within France. It was mixed medical and surgical intensive care unit population. The intervention patients were randomized one-to-one to either baclofen or placebo, and their primary outcome was looking at the occurrence of greater than or equal to one agitation-related event during the treatment period. Patients were enrolled if they had to meet each one of these three criteria. So age between 18 and 80 years old, they had to have mechanical ventilation for at least 24 hours, and they had to meet the specific criteria for unhealthy alcohol use, which was identified either to a patient prior to mechanical ventilation or by family members. So it was dependent upon sex as well as age, ranging anywhere from 7 units to 14 units per week, depending upon if they're male or female. Patients were excluded. They had a pretty lengthy exclusion criteria list, but most notably, if patients were on baclofen prior to ICU stay, if they had any sort of mental health disorder, or if patients were admitted to the intensive care unit for any sort of brain injury, like stroke or hemorrhage. Also notably, baclofen was only administered orally in this study, so if they lacked enteral access, patients were also excluded from the study. The study protocol included on day one of enrollment, patients were given a single loading dose of baclofen that ranged anywhere from 50 to 150 milligrams per day, and this was continued between days two to 15, and they were anywhere the dosing ranged from 50 to 150 milligrams per day in three divided doses based on a patient's renal function. Now, if patients were continued up until day 15, baclofen was then tapered over the next three to six days, and then finally, if patients were either extubated, they required tracheostomy, or discharged from the ICU prior to day 15, baclofen was discontinued. Now, this chart kind of outlines the full study protocol that was provided in a supplemental index, and it just kind of helps to characterize what the different creatinine clearances were that these patients were dosed their baclofen based on, and then also what the gradual taper looked like in these different patient populations. Of note, the sedation was titrated based on a RAS goal of negative two to plus one. The baclofen was not specifically tapered to the skull, but there are other sedative agents. Now, once patients were extubated, they were still monitored based on the CWOP protocol. The outcomes of this study, the primary outcome was evaluating the incidence of agitation-related events over the treatment period, and this is defined as outlined on the slide. So any unplanned extubation, pulling out lines, catheters, or drains, falling out of the bed, leaving the ICU against physician's advice, removing any type of immobilization devices, and then aggression towards themselves or the medical staff. They did have a wide array of secondary outcomes, which we'll discuss in upcoming slides. Of note, they detected that they required at least 314 patients were needed to detect a 15% difference in agitation-related events between the baclofen and placebo group. In terms of the results of the study, so the demographics, these patients were well-matched at baseline. So there were 159 patients in the baclofen group and 155 in the placebo group. They were mainly male gender between the ages, range between 50 and 60, and these patients had well-matched demographics. But of note, they were more medical-intensive care unit patients compared to surgical at around an 80 to 20% ratio. The most common cause for ICU admission was ARDS and septic shock, with a smaller proportion of them being trauma-related admissions. So further demographics of note, the sedatives that these patients received, up to 70% of them did receive benzodiazepines, and this was mainly noted to be midazolam infusions. Furthermore, their second sedative agent was propofol and analgesics, mainly opioids, Sufentanil being the agent that was most commonly used. The RAS score on day one, when these patients were started on baclofen, was negative three to negative five in up to 75% of patients, and around 17 to 12% of patients did require renal replacement therapy. Now, treatment adherence in the baclofen group was only 34%, compared to 44% in the placebo group, and treatment duration ranged anywhere from seven to eight days. So looking at the primary outcome, baclofen did result in a statistically significant reduction in the incidence of agitation-related events compared to placebo, at 19.7% compared to 29.7%, respectively. And even included in the per-protocol analysis, when patients had to have 100% adherence to the treatment protocol, this statistical significance did remain. In terms of the details of agitation-related events, patients were, the most common reduction in agitation was due to unplanned extubation, as well as pulling out any lying strains or catheter. As you can see, they were decreased by around 50% in both groups. In terms of the secondary outcomes, which I think is a really important thing to note about this study, is that while they had a multitude of secondary outcomes they evaluated for, the ones that were of most statistical significance was the total number of agitation-related events at 28% The total number of agitation-related events at 28 days were significant between the groups and reduced in the baclofen-treated arm. However, the duration of deep sedation was prolonged in the baclofen-treated group, as well as there was a prolonged duration of mechanical ventilation, a reduction in ventilator-free days, and finally a prolonged length of ICU stay in the baclofen-treated group. Adverse events that required discontinuation, as noted, there was a statistically significant difference in the duration of deep sedation, so these oftentimes did warrant these patients to discontinue therapy early. Of the total adverse events, 15% of patients in the baclofen group did experience an adverse event requiring discontinuation, compared to 4.5% in placebo. Delayed awakening was the most common cause, with 9% in the baclofen group. Delayed awakening was defined as not being able to open your eyes for at least 72 hours after sedation interruption. So the authors concluded, based on the findings of this study, that among patients with alcohol use disorder receiving mechanical ventilation, high-dose baclofen did result in a significant difference in the reduction of agitation-related events. However, given the totality of the secondary outcome findings and the adverse events that occurred in the baclofen-treated arm, that further research is warranted to determine the role of baclofen in this setting and to help optimize dosing strategies. So I just want to kind of poll a question before we jump into the strengths and limitations of this study. So based off of what you heard about this study, would you currently utilize high-dose baclofen for prevention of alcohol withdrawal-related agitation events in your practice? Yes or no. It seems like a large proportion of us is saying no. And I would agree with you at this point in time with based on what the evidence suggests from this study. So from there, I'll kind of jump into some of the limitations that I found with this trial. In terms of the strengths, it was a very well-designed study. So it was a large multi-center, double-blind, randomized controlled trial with a very protocolized treatment strategy for the utilization of baclofen. And they had a diverse patient population with clear stopping protocols. And I think it was great that they ensured all patients were discontinued off baclofen prior to ICU discharge. Now, in terms of the limitations, now, while this study did detect statistical significance, remember, they did look for a difference. They were evaluating to assess a 15% difference that the study was powered to detect. And they, in fact, did not find that. So the difference was only 9.93%. Furthermore, the primary outcome of agitation-related events, it may not be specific enough to alcohol withdrawal-related manifestations. So not really sure if this primary outcome was best correlated with what we were looking for in terms of alcohol withdrawal-related manifestations in the ICU. Furthermore, ensuring patients all had, you know, preventative delirium strategies in the intensive care unit was not well-defined by the authors in their specific protocol. Furthermore, patients in the baclofen-treated group did experience a prolonged duration of deep sedation, which may have led to the reduction in agitation-related events. But does that really benefit if the risks of prolonged duration of mechanical ventilation and ICU length of stay? I think those risks likely outweigh the benefit in that case. And then finally, the protocol was designed as a preventative approach, which does not currently follow guideline-based treatments, which we try to ensure patients develop manifestations prior to initiation of treatment for alcohol withdrawal in the ICU. So I think optimizing future study designs, kind of defining our patient population a little bit more and including both non-mechanically ventilated ICU patients and then excluding those requiring deep sedation so that there's less confounding in terms of those patients that did experience prolonged deep sedation. I think dose optimization would be really important for future studies, given the max dose in the United States is 80 milligrams per day. So possibly more of a start low and titrate strategy based on RAS or CY like we do with other types of sedative agents. I think ensuring preventative measures for ICU-related delirium would be an important thing to incorporate into future study designs. And then finally, looking at some different outcomes like reduction in benzodiazepine requirements or specific manifestations to alcohol withdrawal like delirium tremens or alcohol withdrawal-related seizures. So in conclusion, is Baclofen in or out for the prevention of alcohol withdrawal manifestations in the ICU? I'd kind of go with out for now and not recommend routine use given the uncertainty of the benefit and the potential risks like prolonged length of ICU stay, mechanical ventilation from the deep sedation. However, I think this could be a potential adjunct agent with symptom-triggered therapy with benzodiazepines if they fail standard-based treatment options. But I think a really important thing to think about if employing Baclofen in your clinical practice would be dose optimization and titration to mitigate the risk of over-sedation while maximizing the efficacy in this patient population. So at this point in time, I'd be happy to take any questions. Thank you, Dr. Barlow. We do have a couple of questions in the panel. So based on this study and previous smaller studies on the topic, would you recommend Baclofen as an adjunct in alcohol use disorder management? And would you limit the application to only MICU and SICU populations versus other ICUs such as neuro-ICU? I think that's a great question. And I think based on this study, it's kind of, it was a little bit hard to assess, right? Because a lot of these patients did receive benzodiazepines. So kind of which one is causing the deeper sedation in this type of setting? I am kind of concerned with the outcomes regarding the adverse effects in the patient population. So I think in those patients that are, I would not use it as prevention. I think that's kind of my major conclusion I would use for this. But in patients who are suffering from manifestations of alcohol withdrawal syndrome, I think it would be unhelpful adjunct if they fail other agents. But I think utilizing our first lines with benzodiazepines would be important. But if they fail some of those traditional agents requiring high doses of benzos, then employment of Baclofen could be helpful. Great, thank you. The next question is, why do you think patients did not receive less sedation in the Baclofen arm if they were more deeply sedated? And do you think a lower dose would have different results? I think that's a good question. The one thing I was unable to elicit from some of the supplemental appendix was they did not exclude patients that did require deep sedation. So it was kind of a little bit unclear to me about how many patients in each group did actually require RAS of negative three to negative five. So I think that was a little bit confusing to me, but I think one of the reasons why they probably didn't require less sedative use, it's kind of a good question because it's unclear why the Baclofen wasn't tapered sooner. So honestly, I'm not sure, but it's a good question. I think understanding some of the underlying indications for deep sedation would have been very helpful. All right, what are your thoughts on the inclusion criteria in identifying patients who might go through alcohol withdrawal that require Baclofen prophylactic treatment? Yeah, so I think that was a big discussion. I know there was a couple of corresponding papers to this article and that alcohol withdrawal, this patient population, so requiring 14 units or seven units, actually patients may not be at high risk of alcohol withdrawal. So maybe this patient population may have been at lower risk compared to patients who do take in higher alcohol. So I think identifying at-risk patients can be challenging, but this patient population may have been relatively at low risk. Great, the next question is what line adjunct would you consider Baclofen in comparison to other options such as phenobarbital, dexmedetomidine, or ketamine? Yeah, that's a great question. I kind of feel like it depends on, so does the patient have an enteral access? I feel like all of these, this is probably the first randomized control trial compared to those other agents that may not have randomized control trial evidence, but I feel like these kind of all have different lines of therapy. I think in patients that have enteral access, this only looked at them, patients who were mechanically ventilated. So if we need an adjunct and if they're requiring very high IV sedative doses, maybe those patients who were trying to minimize fluid exposure, et cetera, Baclofen may be considered a potential option, but I'd consider it maybe like third or fourth line in my current armamentarium. Great, and the last question before we move on is the Baclofen regimen recommended seemed to be complex. Would you make any changes to the regimen used to simplify it? It did seem very complex, but I think they did a very good job at considering the renal function in this patient population, which is probably one of the risk factors for over sedation if patients are not appropriately dose adjusted with the Baclofen. Would I make any adjustments to it? Not necessarily. Maybe I think just utilizing a lower dose would be the most important and titrating it based on a patient's kind of rest and how their sedation, how sedated they are with the Baclofen use. Great, that concludes our Q&A session. Thank you, Dr. Barlow. Now I'd like to introduce our final presenter, Callie Curran. Thank you for the introduction. My presentation today will be on the effect of intermediate dose versus standard dose prophylactic anticoagulation on thrombotic events, extracorporeal membrane oxygenation treatment or mortality among patients with COVID-19 admitted to the intensive care unit, otherwise known as the INSPIRATION trial. So some background for this trial, the results of a 2020 systematic review had actually looked to describe the incidence of venous thromboembolism or VTE on our critically ill patients with COVID-19. And from the systematic review, they found it to be as high as 28%. However, more recent results from a retrospective cohort study this past April had found that the incidence of VTE patients with a positive SARS-CoV-2 infection with a positive SARS-CoV-2 was around 0.8%. Given the lack of consistent results from these smaller randomized trials and some of the observational studies that we have, this has led to some uncertainty regarding the most optimal prophylactic anticoagulation regimen for our critically ill patients with COVID-19. So reviewing some of our current guideline recommendations that we have, the American Society of Hematology makes a statement suggesting the use of prophylactic intensity over intermediate intensity or therapeutic intensity anticoagulation for patients with COVID-19 who do not have suspected or confirmed VTE. The American College of Cardiology makes statements regarding high-risk patients that are admitted to the intensive care unit The American College of Cardiology makes statements regarding high-risk patients that are admitted to the ICU with COVID-19 should get pharmacologic VTE prophylaxis. They do state that there's insufficient data to recommend the routine use of intermediate dose or fully therapeutic doses of heparin for VTE prophylaxis. And lastly, the Society of Critical Care Medicine states that for adults with severe critical COVID-19, they recommend using pharmacologic VTE prophylaxis over not using prophylaxis. So to review some of the available literature that we already have, a systematic review and meta-analysis from 2020 looked to analyze the incidence of VTE and bleeding among hospitalized patients with COVID-19. Looking at a primary outcome of the incidence of non-fatal or fatal VTE during hospitalization, they found that the incidence of VTE for patients in the ICU was 27.9%. The highest incidence estimate of bleeding was in patients that were receiving intermediate or full dose anticoagulation. An additional study that was a retrospective review from 2020 looked to assess the association between anticoagulation and survival for hospitalized patients with COVID-19 looking at an outcome of in-hospital mortality and median survival. This study found that there was a decrease in in-hospital mortality from 29.1% compared with 62.7% and also found an increased median survival of 21 days versus nine days. So we'll start with the first polling question. So in patients with a creatinine clearance of greater than 30 mLs per minute and a BMI less than 40, which of the following would be your preferred method of anticoagulation in a patient with COVID-19 admitted to the ICU? So, it seems like the majority of responders have picked enoxaparin 40 milligrams daily, which seems to be the most common response and common form of practice currently. So, the clinical question from this study was to say, what are the effects of intermediate dose compared with standard dose prophylactic anticoagulation in patients with COVID-19 The authors of this trial hypothesized that intermediate dose compared with our standard dose prophylactic anticoagulation will have superior efficacy with respect to a composite of adjudicated arterial thrombosis, VTE, initiation of ECMO, or all-cause death at 30 days. So, this was an open-label, multi-center, randomized control trial that had a two-by-two factorial design. They randomized 562 patients between July and November of 2020 within 10 centers located in Iran. The main inclusion criteria for this study were adult patients, they had to have a PCR-confirmed COVID-19, they needed to be admitted to the ICU within seven days of the initial hospitalization, and they had to have an estimated survival of at least 24 hours. Some of the key exclusion criteria that I wanted to note were that patients were excluded if they had a weight less than 40 kilos, if they had overt bleeding at the day of enrollment, or if they had a known major bleeding within 30 days. Patients were also excluded if they had platelet counts less than 50,000, or if they had a coexistence of severe obesity, which the authors defined as greater than 120 kilograms, or a BMI greater than 35, along with a creatinine clearance of less than 30 milliliters per minute, and additional indications for anticoagulation, such as AFib, or a history of VTE. So, the interventions performed during this trial were based upon renal function and obesity. So, with the interventional arm, if they had appropriate renal function or a creatinine clearance greater than 30, the standard was anoxaparin one milligram per kilogram daily, and this was compared with anoxaparin 40 milligrams daily. If patients were obese and had appropriate renal function, the dose was anoxaparin 0.6 milligrams twice daily, and this was compared with anoxaparin 40 milligrams twice daily, and then the rest of the interventions were based on patients that had lower renal function, and the dose of Lovenox was adjusted accordingly. So, the primary efficacy outcome for this study was a composite of adjudicated acute VTE, arterial thrombosis, initiation of ECMO, or all-cause mortality. Some secondary efficacy outcomes that they looked at were all-cause mortality, adjudicated VTE, and ventilator-free days. So, for the statistical analysis, they used a modified intention to treat population for the primary analysis. They did assume a 55 percent event rate for the primary outcome with the standard dose prophylactic group, and an absolute risk reduction of the primary endpoint in the intermediate dose group was found to be 12 percent. They calculated that they would need 544 patients to have 80 percent power in order to detect a significant difference, and they enrolled about 600 patients in order to account for a 10 percent dropout rate. They assumed event rates of 5.5 percent and 6.5 percent in the standard dose and intermediate dose anticoagulation, respectively, for major bleeding, and then a 79.5 percent power to detect the non-inferiority of the intermediate anticoagulation. So, looking at some of our patient demographics, I wanted to highlight some of the most important ones. So, looking at our body mass index comparing the intermediate and standard dose, these are overall not a robust amount of obese patients, which is primarily one of the target patient populations that are more prone to thrombotic events, especially in the setting of COVID. I also wanted to highlight that current smoker was around 21 to 35 percent in both of these groups, so those patients may also be at a higher risk for thrombotic events. And then lastly, I wanted to highlight that the venous thromboembolism was zero in both groups at baseline. Additionally, some key findings. So, looking at the baseline indicators for illness severity, vasopressor agents within 72 hours was around 22 percent in both groups. And then looking at the APACHE-2 scores for both groups, these were roughly around 8 percent with both of these groups. They broke it down for acute respiratory support. Looking at our non-invasive ventilation, the majority of the patients in the intermediate dose group had non-invasive ventilation as compared with standard dose, and then invasive ventilation was roughly around 20 percent in both groups. The lab values I did want to highlight were the creatinine. So, most of these patients did have pretty stable renal function, as evident by the creatinine of 1.1 in both groups. And then just to note, the D-dimer was roughly 1,000 in both of these groups as well. So, looking at the primary outcome, this was the compositive adjudicated acute venous thromboembolism, arterial thromboembolism, or treatment with ECMO or all-cause mortality. There was no statistically significant difference. This was 45.7 percent versus 44.1 percent. Looking at our secondary outcomes for all-cause mortality, again, we see no difference between the two groups. Mortality here was roughly around 43 percent versus 41 percent. Adjudicated venous thromboembolism, again, did show no statistically significant difference between both groups, roughly around 3.3 and 3.5 percent in each. And then for ventilator-free days, there was no difference between either group, both showing 30 days for each. And I've included this chart from the trial itself just to highlight that the peak for mortality did seem to occur for these patients at around day five and ten. And I think that's just kind of a key finding to pay attention to, thinking about the decompensation of these patients. So, looking at our safety outcomes, for major bleeding, they did not find a difference between the two groups. They found no difference in the rates of hemoglobin drop, intracranial hemorrhage, or fatal bleeding. For clinically relevant non-major bleeding, they did not find a statistically significant difference either. It was 12 versus 5. And then for the compositive major and non-major bleeding, again, we see no statistically significant difference. This was 17 versus 9. And then for clinically significant bleeding, this was bleeding that warranted attention from the medical personnel but didn't fulfill the criteria for major bleeding. So, the authors concluded that intermediate-dose prophylactic anticoagulation does not improve all-cause mortality and VTE. There's an increased percentage of major and non-major bleeding with intermediate-dose anticoagulation and an increased severe thrombocytopenia rate with intermediate-dose anticoagulation. So, reviewing some of the strengths and weaknesses of this trial, some of the strengths were that this was the first large randomized control trial that compared intermediate versus standard-dose prophylactic anticoagulation, which has been a question that has been very popular since the beginning of COVID. They also had very relevant clinical outcomes in terms of the objectives they were aiming for. And they objectively had a confirmed diagnosis using the COVID confirmed diagnosis by PCR. They also had adjudicated outcomes to help remove subjectivity. Thinking about our weaknesses for this trial, I think one of the weaknesses to consider is that they used intermediate dosing of one milligram per kilogram daily. And I think it brings up the question of whether or not this is appropriate intermediate-dose anticoagulation because this definition is very variable across different institutions. Personally, at our own institution, for our intermediate dose, we use 40 milligrams of inoxaparin twice daily. I believe that the inclusion and exclusion criteria for this trial did contribute to a lower acuity patient population as well. And I think something else that's important to note here is that they did lack a lot of obese patients based on the BMIs of around 25 and 26, which obese patients can be at higher risk for thrombotic events. I think the concomitant use of steroids may have mitigated some of the adverse inflammatory effects that could increase the risk of thrombotic events. And then the high mortality rate was pretty unusual compared to some of the other COVID-19 trials that we see. They did have a mortality rate of around 43 and 41 percent for both groups, which is a little higher than what we've seen in some of our other studies. And lastly, I think ECMO is a questionable weakness of this trial. I think it's an interesting outcome to evaluate. So I thought that was just some of the weaknesses. And I think it's a very extrapolated outcome that they're trying to look for as well. So based on the findings of the current study, would you consider using enoxaparin one milligram per kilogram daily intermediate dose prophylactic anticoagulation for patients with COVID-19? This is interesting, so it seems like the responses favor more towards either no or needing more data, and I would tend to agree with needing more data. I think it's just interesting that we have very few that responded yes, so I think this varies depending on the institution, and it's interesting to see where we go with practice with the more data we acquire moving forward. So, some takeaway points. There's uncertainty that still remains in regards to the most optimal prophylactic anticoagulation strategy for these COVID-19 patients. The results of this study do not support the routine use of intermediate dose prophylactic anticoagulation in patients with COVID-19 that are admitted to the ICU, and I believe that additional studies are needed to be able to evaluate the role of anticoagulation in COVID-19 patients with higher risk factors that may predispose them to VTE. So, thinking about our obese patient populations, our patient populations with a history of cancer, or other high-risk factors that may predispose them to thrombotic events. And at this time, I would be happy to take any questions. Thank you, Dr. Curran. It looks like we do have a couple of questions, the first being if you could discuss where the authors developed the intermediate prophylactic recommendations, specifically the anoxaparin 0.6 milligram per kilogram BID for obesity with preserved renal function. Sure, I think that's a great question and something that I was questioning myself when reading this trial. It was listed in their interventions, however, there was no real good description of where that dosing strategy kind of came from, so that would be something interesting to explore further. The next question is if you could comment on whether the difference in bleeding between the groups was clinically different or not. Sure, I think that based on the results we saw here, there was a trend towards increased bleeding with the intermediate dose anticoagulation, however, it didn't appear as though this led to any harmful patient outcomes. So clinically, I think it's hard to make a confirmed statement on that. Given the lack of outcomes that were harmful for patients, I would say it may not be as clinically significant. I think what's important to note, too, is that here they used the BARC criteria, which is the Bleeding Academic Research Consortium, and this has a different criteria compared to some of the other studies that we use. A lot of other studies look at defining bleeding as major or minor bleeding, however, this is more of an objective approach to analysis of the bleeding, so I think that that also helped to really analyze whether or not this was a clinically relevant bleeding. All right, our last question is, what BTE prophylaxis dosing does the Anticoagulation Forum recommend in COVID-19 patients, and how does that differ from the dose, or rather doses, used in this trial pharmacokinetically? I'm sorry, can you clarify the dosing coming from where? The Anticoagulation Forum. Yes, specifically for COVID-19 patients. Sure, to be honest with you, I'm actually not familiar with what dosing strategy they use, so I'm afraid I'm unable to comment. Okay, no problem. Our last question is from Dr. Smith, so based on these trial results, what would you recommend for obese populations based on previous data with anoxyparin prophylactic dosing? Sure, I think right now we still don't have a lot of strong data, especially in our COVID-19 patient population, so COVID-19 patients that are of a higher BMI that are classified as obese, I think my strategy would tend to be to prefer to continue to use the intermediate dose, given the fact that the risk of bleeding was not statistically significant here. I think that these patients are at a greater risk of thrombotic events, which we have seen outside of just COVID in itself, so I think my strategy would still be to prefer to use the intermediate dose, regardless of the outcomes that this trial had shown, and I think we do need more data moving forward to get a better analysis on the impact of intermediate dose, especially in COVID-19 for these patients. Great, thank you. That will conclude our Q&A session. Thank you to our presenters today and audience for attending. Please join us on the third Friday of the month from 2 to 3 p.m. Eastern Standard Time for the Next Journal Club Spotlight on Pharmacy, and that will conclude our presentation today.

Journal Club Spotlight on Pharmacy

critical care medicine

hat therapy

sepsis

septic shock

baclofen

alcohol withdrawal

ICU

prophylactic anticoagulation

COVID-19 patients