So, 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 Alexandra Barber. I'm a medical ICU critical care pharmacy specialist at Atrium Health Wake Forest Baptist Medical Center in Winston-Salem, North Carolina. I'll 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 that will be on the right-hand side. You will also have the opportunity to participate in several interactive polls. When you see a poll, simply click the bubble next to your choice. You may also follow and participate in live discussion on Twitter, following hashtag SCCMCPPJC and hashtag FarmICU. SCCM provides the following disclaimer. The 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, physician, product, procedure, opinion, or other information that may be mentioned. 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 Kaitlyn Fellers, a PGY-2 critical care resident at University of Alabama at Birmingham Hospital in Birmingham, Alabama. Our second presenter is Alyssa Megan, a PGY-2 critical care resident at Jackson Memorial Hospital in Miami, Florida. And our third presenter is Jill Davenport, a PGY-2 critical care resident at ProMedica Toledo Hospital, Russell J. Abed Children's Hospital in Toledo, Ohio. And now I'll turn things over to our first presenter, Kaitlyn. Thank you so much for having me today. Like Aly said, my name is Kaitlyn Fellers, and I will be talking about the impact of opioid administration in the intensive care unit and subsequent use in opioid-naive patients. Just a disclosure, I don't have anything to disclose regarding anything I will be talking about today. So first I wanted to start off talking about the opioid epidemic. The CDC recognizes three different phases of the opioid epidemic, the rise of prescription opioids in the late 1990s and early 2000s, and then the rise of other synthetic opioids with fentanyl and tramadol and heroin within probably the last decade. With this increased use of opioids, roughly 136 people die every day from an opioid overdose, and that includes prescription and illicit opioids. With the continued acknowledgement of this opioid epidemic, I think it's important as critical care pharmacists to evaluate the way we utilize opioids for patient care to determine how our practices are contributing to prescription opioids and the potential risks for opioid overdoses. And to adequately address this, I think it's important to evaluate how opioids are utilized within the intensive care unit. Of course, we're using opioids for acute pain where there is actual structural damage to the tissue inciting a biological response, which can eventually progress to chronic pain where opioids can take part in multimodal pain management. And depending on why the patient was admitted, such as for respiratory reasons, surgery, or trauma, there might be a direct correlation to the use of opioids and prescription opioids at discharge. There is literature to support the use of opioids in both surgical and trauma patients to be utilized in that multimodal pain management. Another reason for the utilization of opioids in the intensive care unit is for analgesia first approach for sedation, which is recommended by the pain, agitation, and delirium guidelines from SCCM. They recommend the use of IV opioids as first-line therapy for non-neuropathic pain and to assess pain management with either the numeric pain scale or critical care pain observation tool to potentially manage pain or discomfort while in the ICU. And we know from the CDC that there is data demonstrating that approximately 10% of fatal overdoses occur in patients released from institutionalized settings in the month preceding the overdose. And so in response to this opioid epidemic and opioid overdoses, the Joint Commission has released standards for pain assessment and pain management in hospitalized patients. This includes identifying pain assessment and pain management tools and safe opioid prescribing as organizational priorities. And this continues through the assessment and management of the patient's pain meds, but also collecting data to monitor the hospital's performance and analyzing that data to making sure that we are making the most appropriate opioid prescriptions. So the trial that I'm examining today is the impact of opioid administration in the intensive care unit and that subsequent use in the opioid-naive patients. And so the authors really wanted to evaluate the relationship between utilization of opioid administration in the intensive care unit in those opioid-naive patients and to see how that influences the subsequent opioid use at discharge. This was a retrospective multi-center cohort analysis of three different community teaching hospitals that included medical, surgical, and cardiac ICUs. Now these patients received fentanyl, hydromorphone, or morphine, with roughly 98% of patients actually receiving fentanyl. And this was completed through July 1st of 2011 through June 30th, 2018. The patients that they included were 18 years and older who were described as opioid-naive. And then the way they defined this was the absence of opioid prescriptions within the preceding six months and no documented opioid use. They excluded patients who were being discharged to long-term acute care hospitals, hospice, or correctional facilities if the patient was transferred to another hospital for continued care or if anybody was receiving intrathecal opioid therapy. And they took these groups of patients and they actually split them into patients who received opioids at discharge versus patients who did not receive opioids at discharge. Their primary outcome that they used to evaluate this relationship was they wanted to evaluate the relationship between opioid morphine milligram equivalent, so MME, administered within the ICU, and then what was the opioid MME at discharge to potentially see if there was a relationship there. And their primary outcomes included relationship between ICU opioid exposure and opioid prescriptions at discharge, as well as incidence of long-term opioid use. For their statistical analysis, they used linear regression for their primary outcomes and multivariable logistic regression analysis for their secondary outcomes. And they calculated that they needed 342 patients to meet 80% power. The patients that included, they found that the age was a significant difference between the two groups with higher age and the no opioid prescribed at discharge versus a younger age with opioids prescribed at discharge, as well as there being significant difference in the admission diagnosis. So as you can see, more patients had no opioids prescribed at discharge were admitted for respiratory reasons versus if they did have respiratory reasons, they had opioids prescribed at discharge. And then this is kind of reflected the other way for surgical and trauma slash orthopedic with more patients being prescribed opioids at discharge than not having opioids prescribed at discharge. And lastly, another baseline characteristic that was significant is more patients were sent to a facility that had opioids prescribed at discharge than they were sent home. Some other key baseline characteristics is the actual ICU type on admission with a higher amount of patients in medical ICUs being not prescribed opioids at discharge with higher amount of surgical patients actually being prescribed opioids at discharge. They also evaluated the severity of illness of these patients with a sequential organ failure assessment score, which they found to be significant with five for the no opioid prescribed at discharge. So more patients were sick and the severity of illness was higher in the no opioids prescribed at discharge than with opioids prescribed at discharge. However, there was only one point of difference and they didn't mention what the actual difference or the highest difference was in these patients. And lastly, for opioid exposures, total ICU opioid MMEs was 750 for the no opioid prescribed at discharge, but 935.4, which was significantly different, as well as the use of intermittent MMEs, which was higher on the opioids prescribed at discharge. Lastly, they evaluated the fentanyl infusion duration and number of hours, which they did not find to be significantly different in the two groups. So for their primary outcome, they were looking at a relationship between the total or daily ICU MME while the patient was inpatient and to the daily MME at discharge, and they failed to find a relationship between these two with the R-squared for total being roughly 0.008 and then the R-squared for like actual daily ICU MME being 0.003 on the linear regression model. They did complete a multivariant logistic regression model for their secondary outcomes with the main point variable being where they prescribed opioids at discharge. And so for discharge opioid prescriptions, they found that age was protective for these groups where the older patients did not receive opioids at discharge and for related admission diagnosis, they found respiratory was also protective. For surgical trauma and malignancy, they found that these patients were more likely to be prescribed opioids at discharge. Another discharge opioid prescription variable was non-ICU length of stay, and patients who were in the hospital longer, not necessarily in the ICU, but in the hospital longer, actually was a significant predictor for opioid prescription at discharge. And then one of their secondary outcomes was long-term opioid use and the only significant factor for this was the receipt of opioid prescriptions at discharge with an odds ratio of 4.15. In summary, they found no significant relationship between total ICU MME and the receipt of an opioid prescription at discharge or the incidence of long-term opioid use. Some significant predictors of opioid prescription at discharge include longer non-ICU length of stay and a related admission diagnosis of surgical trauma or malignancy. They also found that age potentially reduced the likelihood of opioid prescription at discharge. And lastly, they did find that one of the significant predictors of long-term opioid use was the receipt of discharge opioid prescription. So for the strengths of this article, I did find that the association between ICU MME to home MME was definitely a strength. This is one of the first trials that I'm aware of or retrospective chart reviews that tried to see how MME influenced if patients were prescribed opioids at discharge or at least influenced the total MME. Also, the separation of units to know how many patients were in medical ICUs or surgical or trauma because we already, there is previous literature to describe the use for in surgical and trauma patients. And lastly, the use of the logistic regression model to account for those various variables, I think was a strength of the study. But some limitations, they did not follow with discharge diagnosis even though they did have admission diagnosis. And just because a patient is admitted for respiratory reasons doesn't mean that they're not going to undergo a surgery or have need for opioids at discharge. So kind of to see how the patient was discharged, I think would be important. And they were also unmatable to utilize the prescription drug monitoring program in their state. They assessed limited safety outcomes, which I think would have potentially highlighted some of the things that we could do within the ICUs to influence our safety outcomes. And lastly, they needed 346 patients to meet their power analysis of 80%, but they only included 342. Now, this is only a difference of four patients and I don't think it had any influence on their outcomes, but I do think it's important just to state because they did complete a power analysis. And lastly, they didn't include what their multimodal pain management was utilized for these patients or kind of examine it across the three hospitals. And I think it would be interesting to see how the difference in multimodal pain management might have influenced whether patients were going to get opioids at discharge or not. So for future directions and how I'm going to use this in my own practice as I build it up going through the last half of my PGY-2 year and into my practice, reexamining the use of IV pushes versus enteral opioids and various continuous infusions. I know where I currently am doing my practice. We use a lot of enteral opioids for discontinuation of continuous infusion opioids for our patients to make sure that we are appropriately managing their pain and withdrawal as we quick taper down their continuous infusions. And potentially there could be a standardized process for each ICU or even an institution to address opioid weaning if we're utilizing it for an analgesia first approach for sedation. And lastly, continuous monitoring of opioid indication. So if we did schedule enteral opioids for these patients to potentially wean them off and they are off and ready to transition to their floor or step-down unit, we need to be continuously monitoring, are those opioids appropriate for this patient? Are we adequately treating their pain if they do have pain? And is there an indication so that when we do complete the transitions of care and they transition into the floor and step down and potentially discharge, they're not being given medications that we used due to withdrawal and it's appropriate. So for my first polling question, which options below describe your preferences to aid in weaning opioid infusions in mechanically ventilated patients? Say you have a patient who is just like difficult to withdraw or is having pain that prohibits successful extubation, what is your preference? Or if you have multiple preferences, I understand that too. So it looks like a majority of the attendees or 89% say enteral opioids, which is I know what I've seen used here in our practice with roughly 6% using IV push opioids. I don't know if it's necessarily y'all's preference or provider preference or if you found benefit, but I think it's really interesting to see the kind of differing answers that everybody put. The next polling question is, does your institution have a process to facilitate weaning opioid infusions? And this could be a standardized process or a process that you and your pharmacy colleagues have come up and say that we're going to be utilizing this for our patients. It looks like a majority says no, with some people saying yes or it depends. I think as we kind of continue on through our practice, it'd be definitely interesting to see if processes come available and how different people wean their opioid infusions. So thank you so much for answering those polls. So I just wanted to thank you all for allowing me to present. I also wanted to thank my mentor, Zachary Smith, for helping me with this patient safety topic discussion and all of my preceptors and RPD at my institution who helped guide me through this presentation. Thank you so much. All right. Well, thank you so much, Kaitlin. That was an excellent presentation. Next, we will go ahead and open up the Q&A session, picking your brain about how your institution is handling this, especially as we're seeing higher pain and sedation requirements for some of our COVID-19 patients. Is there any methodology that you or your institution is using as a whole to notate when you're using those enteral opioids to help wean down sedation, that these need to be continued to be weaned when the patient leaves the ICU? Have you guys used any good transitions of care tips that you can share with us? So I definitely have experience during my medical ICU rotation. I took care of quite a few COVID patients, and we were using enteral opioids. Our preference is oxycodone to help wean off these patients who are on long-term hydromorphone at very high doses. Typically, for our patients, we were able to kind of transition them onto enteral opioids. And then as they were weaning the hydromorphone or fentanyl, if that was needed, we would wean within like every 24 to 48 hours by decreasing the interval. And then by the time we decreased the interval from like Q4 to Q6 to Q8, then we would decrease the dose. Most commonly, I've seen us start at 10 milligrams and then go to 5 milligrams and then eventually PRN. For our patients, the short time I was there, most of them, we were able to wean off the enteral opioids by the time they were ready to discharge to the floor. And I would have to ask our three amazing MICU pharmacists on how they're doing it if patients aren't able to wean off the floor. But I think including is just like pass off to our pharmacists who are getting those patients, letting them know like, hey, this patient is on schedule opioids for the weaning and withdrawal of their infusions. And making sure to have that good pass off, I think, is really important to make sure they're not discharging on them at home. Great. Really good. One more question for you, Caitlin. Based on these findings, is there anything you would change in your practice to prevent inappropriate opioid prescriptions at discharge? If there was anything during my practice, I think the important thing to highlight, which I thought was super interesting, was that non-ICU length of stay being a significant predictor of opioid prescriptions at discharge and kind of echoing the statement that I just had, definitely understanding the very big importance of transitions of care and making sure that there's adequate pass off. And I think as I go into my practice throughout the rest of the year and next year, I'm just going to continuously be evaluating what the purpose of the opioids and why we are utilizing it to make sure that it is appropriate and so that we aren't putting patients on opioids just strictly for pain management and also utilizing those multimodal. I know ketamine hasn't necessarily been studied all that well. I think there's one trial out there that I can recall. But potentially seeing if we can use multimodal pain management, I think, is what I'm going to highlight in my practice. Excellent. Excellent. All right. Well, that will conclude our Q&A session. Thank you again, Caitlin Fellers. Before moving on to our next presenter, we'd 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. Thank you. Now, I'd like to introduce our second presenter, Alyssa Magen. Good afternoon, everyone. My name is Alyssa Magen, and today I will be presenting my journal club on the MAVERICK study, which is a pilot feasibility randomized controlled trial of mitadrine as an adjunctive vasopressor for low-dose vasopressor-dependent hypotension in our intensive care unit patients. I have no potential conflicts of interest to disclose regarding this presentation. The presentation objectives for today are to interpret the previous literature regarding the use of mitadrine for vasopressor weaning in the ICU, as well as develop a recommendation for adjunctive mitadrine use in persistent vasopressor-dependent hypotension without any evidence of organ dysfunction, more often known as vasoplegia. Vasopressor-dependent hypotension after shock resolution is often a barrier to ICU discharge for our patients, and thus this can lead to prolonged ICU length of stay, which can lead to various complications, including ICU-acquired delirium, as well as hospital-acquired infections as well. Our adrenergic agents are hypothesized to facilitate vasopressor weaning and allow patients to be discharged from the ICU quicker, since our IV vasopressors are only administered in critical care settings or in the emergency department. Thus, the off-label use of mitadrine as a vasopressor weaning agent has grown in the ICU setting, despite limited evidence supporting its use. Now, just some information regarding mitadrine. It is an alpha-1 agonist that increases our systemic vascular resistance, and it's favorable in that it's an oral agent that can be administered to patients via oral route or a feeding tube. For dosing for patients, it can be used at a dose of between 10 to 20 milligrams every eight hours. It has been reported for vasopressing sparing therapy at a maximum reported dose of 40 milligrams every eight hours, although we do need to be aware of dose-dependent adverse events, including compensatory bradycardia and supine hypertension. Now, the previous studies assessing mitadrine use in the ICU as a weaning agent are listed here. Dean and colleagues was one of the first that was a single-center prospective observational study looking at 20 surgical ICU patients on vasopressor therapies for at least 24 hours, with a median duration of vasopressor therapy of three days. Patients were administered mitadrine doses between 5 to 20 milligrams every eight hours, in which the modal dose was 20 milligrams every eight hours in this patient cohort. And they had found when comparing pre- and post-mitadrine administration, there was a significant decline in the IV vasopressor rate in those patients. Now, this led to the discovery of other studies, including Winston and colleagues, which is a single-center retrospective cohort study looking at 275 medical ICU patients with septic shock on vasopressor therapy for at least a 24-hour period. Patients were initiated on a mitadrine dose of 10 milligrams every eight hours, and the dose was individualized to patient response. And this was compared to usual care. In regards to the results that they had found, in those patients that were receiving mitadrine, there were significantly higher vasopressor discontinuations, as well as lower ICU length of stay in those that had received mitadrine. And of note, the median dose that patients received was 20 milligrams every eight hours in that cohort. This finally led to the MIDUS trial, which was a multi-center placebo-controlled trial looking at 132 mixed ICU patients receiving single-agent vasopressor therapy for at least a 24-hour period. Patients had a median dose of medium, sorry, duration of vasopressor therapy for at least three days. And patients were randomized to either receive mitadrine 20 milligrams every eight hours that would be titrated off once patients had had discontinuation of their vasopressor therapy versus placebo. Overall, the MIDUS trial had found that there was no difference in time to vasopressor discontinuation or clinical outcomes, such as ICU length of stay or hospital length of stay. However, when looking at the cohort of patients that had received epidural anesthesia, there was a significant difference in time to vasopressor discontinuation in those patients that had received mitadrine. Now we're going to be moving on to discussing the MAVERICK study. As a study overview, the MAVERICK study was a pilot feasibility and physiologic efficacy open-label randomized controlled trial. Its primary objective was to determine the efficacy of mitadrine for low-dose vasopressor weaning. And this was performed at two trial sites in Australia. For patient inclusion criteria, it included adult patients admitted to the ICU that had refractory hypotension, which was defined as IV vasopressor therapy for at least 24 hours, determined to be clinically stable by the treating physician and receiving no more than norepinephrine of 10 micrograms per minute, or metaamaryl, which is an alpha 1 and beta 1 agonist that's used outside of the United States, of 100 micrograms per minute. Patients were excluded if they had severe shock states or organ dysfunction, including renal or liver failure, as well as alternative causes of refractory hypotension, including hemorrhagic shock. Patients were also excluded if they were bradycardic at the time of screening, which was defined as a heart rate less than 50 beats per minute. Patients were randomized one-to-one to either mitadrine, 10 milligrams every eight hours, with ongoing vasopressor infusion versus usual care. And they did have a study weaning protocol performed once patients achieved the primary outcome of cessation to IV vasopressor therapy. So a patient would continue to receive the 10 milligrams every eight hours for 24 hours, and this was tapered off every 24 hours until the patient was off of the therapy. Patients were observed in the ICU for at least eight hours post-cessation of IV vasopressor therapies. Now, for the outcome measures, the primary outcome was assessing time to cessation of IV vasopressor therapy, in which patients had to be off of IV vasopressors for at least an eight-hour period. And secondary endpoints included time to first shock resolution, in which patients had the IV vasopressor therapy discontinued between four to eight hours, as well as other feasibility outcomes, including protocol compliance, as well as adverse drug reactions. Other endpoints included clinical outcomes, such as ICU and hospital length of stay, as well as a change in vasopressor dose and heart rate. In regards to the statistical analysis, it was performed via an intent-to-treat population. And when assessing the primary outcome, the authors had estimated a difference between study arms of 0.9 day difference in time to vasopressor cessation. To achieve such a difference, they wanted to assess a sample size of 30 patients per arm that would give them an 80% power to achieve this difference. Primary outcomes were assessed via the statistical tests analyzed, depending on the type of variable that was assessed. Now when looking at patient enrollment, this was performed over a 22-month period. And unfortunately, the study was terminated early due to the COVID-19 pandemic. 381 patients were assessed for eligibility, in which 319 patients were excluded, a third of which was primarily due to being excluded due to having acute kidney injury. Now 62 patients were randomized, 32 in the mitodrine arm versus 30 in the control arm. And of note, one patient discontinued intervention in the mitodrine arm due to having clinically significant bradycardia. Now when assessing the baseline characteristics, there were no significant difference when comparing the baseline characteristics, as well as comorbidities in the mitodrine arm in comparison to the usual care arm. Of note, those patients in the control arm did have a higher median baseline vasopressor dose at study randomization in comparison to those patients in the mitodrine arm. But this was primarily due to the patient's difference in weights when looking at the two arms. Another important note to assess is that patients were randomized, had a pre-randomization vasopressor duration of approximately 32 hours in both arms. And this is significantly different in comparison to previous trials, such as the MIDUS trial, in which patients had a median pre-randomization vasopressor duration of at least three days. Now when looking at the primary endpoint, there was no significant difference noted in time to achieve cessation of vasopressor infusion in comparison to those patients receiving mitodrine, which was 16.5 hours versus 19 hours in the usual care arm. So it was numerically lower with mitodrine use, but not found to be statistically significant, I apologize, in this study. Now these authors also did perform a linear quantile mixed model in which they adjusted for baseline characteristics as well as comorbidities. And they had found significantly faster decline in vasopressor use in the usual care arm in comparison to the mitodrine arm. Similar outcomes are listed here. There was no significant difference noted in patients receiving mitodrine in comparison to usual care in regards to median time to first shock resolution, ICU, or hospital length of stay. Of note, though, in those patients in the mitodrine arm, there was numerically lower rates of lower time to time for shock resolution, as well as lower ICU length of stay, although the study may not have been powered in order to detect such a difference. Now those patients in the mitodrine arm did have significantly higher rates of bradycardia. However, there were no reported events of severe bradycardia defined by a heart rate less than 40. Also the authors reported a very high compliance with the study protocol, in which 97% of patients completed treatment and 60% of patients completed the weaning protocol. In conclusion, the authors stated that there was no significant difference in time to cessation of IV vasopressors, as well as clinical outcomes such as ICU and hospital length of stay with adjunctive mitodrine use. However, they did report that there was high rates of protocol compliance, showing the high rates of internal validity of the study, as well as low rates of adverse events overall in the study population. However, there were limitations of the trial that they recognized, including the open label trial design, exclusion of patients with acute kidney injury, as well as a small sample size which may have potentially contributed to type 2 error. In regards to the critique of the patient population, some strengths include that the characteristics between groups were well balanced, as well as the comorbidities as well. Also the authors did assess for compounding variables, such as the use of steroids as well as sedatives in the population, and found no significant difference when comparing both groups. They also assessed both medical and surgical ICU populations. Some limitations include that there was poor external validity of the study, in which there were high baseline maps seen in both arms, of which the median baseline map at initiation was approximately 72 in both arms, which makes us question whether the patients really required vasopressor therapy at randomization. Also, they did not report ICU diagnosis other than sepsis, and they had no racial demographics reported. In regards to the interventions, some strengths include that there was high internal validity of the protocol due to compliance reported, as well as they had a uniform waning protocol that was used for all those patients on midodrine. Also, I felt that the choice of midodrine dose that patients were initiated on was appropriate based on bradycardic events that were seen in previous trials. Some limitations of the interventions include the open label study design, which may induce author bias, as well as the limited generalizability due to the unknown nurse-to-patient ratio in these ICUs, as well as how often monitoring was performed. In regards to the endpoints and statistics, some strengths include the appropriate clinical endpoints and statistical tests that were chosen, as well as assessing the population and statistics on an intent-to-treat protocol. Also, they did perform a linear mixed model that was adjusted for baseline characteristics, as well as comorbidities. Some limitations include that the primary endpoint did have a short vasopressor-free window of eight hours in comparison to previous studies, and again, the potential type II error to not detect a difference when there may potentially be within the treatment arms. Now, in conclusion, adjunct and midodrine use in vasodilatory shock patients on low-dose vasopressors was not associated with improvements in clinical outcomes, such as ICU in a hospital length this day, as well as reducing the amount of time to vasopressor cessation. There were multiple limitations that exist for this trial, including its open-label trial design, as well as poor external validity and small sample size. For my clinical application, I would not recommend utilizing midodrine as a vasopressor weaning agent in non-cirrhotic vasodilatory shock patients, and I do believe future research should focus on midodrine use in patients with alternative causes of vasoplegia, including those patients that were receiving epidural anesthesia, or even trying to individualize the dose for patients in comparison to starting them on a higher dose and weaning them off. And now we're going to move on to the polling questions. So for the first one, does your institution utilize midodrine as a vasopressor weaning modality in ICU patients on low-dose vasopressor infusions? Just to provide a little bit of background on my current institution, we do utilize midodrine as a vasopressor weaning modality. However, the dose is often started off lower for patients to avoid bradycardic events. So usually at midodrine, doses of 5 milligrams every eight hours, and titrated up to patient response. Of note, just in regards to the poll results, 79% of individuals did say yes, versus 21% of individuals said no, which I feel is in line with practice that we see nowadays. The second polling question, if so, what dose of midodrine does your institution initiate for most patients? And this is excluding those patients with acute kidney injury. And of note, as I had mentioned previously, at my current institution, those physicians do generally start a dose of 5 milligrams every eight hours and then adjust the dose and individualize it to the patients. And of note, in regards to the poll results, 84% of individuals did state that they start a dose of 10 milligrams every eight hours, which is in line with other institutions, that they do start either between 5 to 10. Some individuals also do start at a higher dose of 20 milligrams every eight hours, similar to the MIDUS trial. And I did want to thank you all for attending my presentation today. And also, very special thanks to my preceptors, as well as my RPD for allowing, for helping me with the current presentation. And I will take any questions you all may have for me. Thank you, Alyssa. So, any questions, you can put them in the question box. You mentioned at the end of your presentation that you would not recommend utilizing midodrine as a vasopressin weaning agent in non-steroidic vasodilatory shock. Are there any specific patient groups that you would consider using midodrine to liberate patients from vasopressors faster or just to liberate them at all, since we don't have the data that says it's faster? Of course. So, there are certain patient populations that I may consider using midodrine in, and this is especially in those patients that were on vasopressor therapies post-surgical intervention, since the MIDUS trial did find that those patients in the subgroup that received epidural anesthesia previously did have a benefit to midodrine therapy with time to vasopressor cessation. So, that's definitely one group that I would utilize it in. Also, when looking at some of our patients that may be on vasopressor therapy for a longer period of time. So, let's say if the patient was on for over a five-day period, that's where I may consider having a trial of midodrine to try to facilitate ICU discharge. And when looking at the current evidence, majority of patients that were assessed, they primarily were started midodrine therapy after a three-day period of being on vasopressor therapy. Other than the MIDUS trial, I'm sorry, other than the MAVRT trial, which I was assessing, which was a total of 31 hours that patients were started on midodrine therapy thereafter. Thank you. Seeing as we don't have any other questions for you, Alyssa, thank you so much. We will move on to our next presentation. I'd like to introduce our final presenter, Jill Davenport. Hi. Thank you for the introduction. My name is Jill Davenport, and I'm the PGY-2 Critical Care Resident for Medical Toledo Hospital. Today, I will be presenting on a trial titled, A Randomized Trial of Intravenous Alteplase Before Endovascular Treatment for Stroke, also known as the Mr. Clean No IV Trial. I don't have any potential conflicts of interest to disclose. Endovascular treatment, or EVT, has become part of the standard treatment for patients who have acute ischemic stroke due to large vessel occlusion in the anterior cerebral circulation, in addition to thrombolytic therapies like alteplase. Alteplase has been shown to improve outcomes in acute ischemic stroke and may increase early reperfusion. However, the lytic effect of intravenous alteplase on large thrombi is limited, and partial lysis could fragment the target thrombus or cause it to migrate distally, in addition to putting patients at risk for bleeding. It is currently recommended by the American Heart Association and American Stroke Association guidelines for the early management of patients with acute ischemic stroke to administer alteplase before EVT in eligible patients. There have been a handful of studies published looking at the safety and efficacy of performing EVT without the administration of alteplase, first in patients with large vessel occlusions in the anterior cerebral circulation due to the risks associated with thrombolytic administration. One of the first studies to come out was the DIRECT-MT trial in May 2020. They did look at 656 patients in China with acute ischemic stroke from large vessel occlusions in the anterior circulation, and they were randomized to receive either thrombectomy or EVT alone, or EVT along with intravenous alteplase. What they found from this trial was that EVT alone was non-inferior with regards to functional outcomes based on the modified Rankin score when compared to the standard of care. This is similar to the results of the DEV trial, which also showed a non-inferiority and 90-day functional independence in 234 patients treated with EVT alone compared to alteplase followed by thrombectomy. And again, this study was conducted in China. The last trial to come out was the SKIP trial, which was conducted in Japan, and they failed to demonstrate non-inferiority of EVT alone compared to alteplase followed by thrombectomy. However, they did utilize a lower dose of alteplase at 0.6 mgs per kilogram compared to the United States standard of 0.9 mgs per kg. So due to this conflicting data and the limited patient population studied so far, the purpose of the MR-CLEAN-NO-IV trial was to determine whether EVT alone would be more effective or non-inferior as compared with alteplase followed by EVT in European patients with acute ischemic stroke due to an intracranial anterior circulation stroke. So from this, the authors hypothesized that admitting intravenous alteplase before EVT would reduce the risk of intracerebral hemorrhage and thereby improve patient outcomes. So for our first polling question, I just want to get a good idea from the audience on does your institution currently provide endovascular treatment? And this will be relevant for this trial just because the data studied so far have only looked at patients that were directly admitted to an EVT-available facility, and so it looks like 80% of our audience today is currently practicing at one of these institutions. For those of you that are not, it is unclear. We don't have data to support that has been investigated leaving out alteplase therapy for this patient population. The design of this trial was an open label with blinded endpoint assessment, and it was international, multi-centered, randomized, and conducted in Europe. Patients were randomly assigned in a one-to-one ratio to receive EVT alone or intravenous alteplase followed by EVT, which is currently the standard of care. Patients were included if they were 18 years of age or older, had an acute ischemic stroke due to intracranial proximal occlusion, which was defined as an occlusion in the intracranial internal carotid artery, the first segment of the middle cerebral artery, or M1, or the proximal second segment of the middle cerebral artery, or M2. Patients were also eligible if they presented directly to a hospital that was capable of providing EVT and if they were eligible for both EVT and alteplase therapy. I hope I apologized. My slides were a little bit faster. The primary endpoint of this study was functional outcome on the modified Rankin scale, which ranges from zero, meaning no disability, to six, meaning death at 90 days. Some secondary endpoints included recanalization on the first intracranial angiogram, successful reperfusion on the final intracranial angiogram, recanalization on CT or MRA at 24 hours, NIH stroke scale score at 24 hours, as well as at five to seven days or discharge, along with some additional endpoints. For safety endpoints, they did include death from any cause, as well as symptomatic intracerebral hemorrhage. So the authors calculated that they would need a sample size of 540 patients to meet power and to detect a true difference in treatment effect. They assessed the superiority of EVT alone over alteplase plus EVT with an intention to treat analysis, as well as non-inferiority with a non-inferiority margin of 0.8. Primary and secondary analyses were adjusted for age, baseline NIH stroke scale scores, collateral status, pre-stroke score on the modified Rankin scale, and time from symptom onset to randomization. They also predefined some subgroups, which consisted of age, baseline NIH stroke scale score, time from symptom onset to randomization, occlusion locations, intracarotid artery tandem lesions, collateral status, and atrial fibrillation. So overall, 539 patients were included in their analysis. For our baseline characteristics, age was slightly higher at a median of 72 years old in the EVT group compared to a median of 69 years old in the alteplase plus EVT group. Both groups did have a majority of male patients, and a majority of occlusions were in the M1 artery. And they had a pre-stroke modified Rankin scale score of 0. 31.5% of patients did have atrial fibrillation in the EVT group compared to 23.7% in the alteplase plus EVT group, which may not have been statistically significant, but it could have been a compounding factor with the percentage of difference noted. The median NIH stroke scale score was 16 in both groups. Pre-stroke MRS scores had about the same distribution in both groups, with the majority of patients being functionally independent at baseline. And the median duration of door-to-groin puncture time was around 63 versus 64 minutes in each group. So for the primary outcome of median score on the modified Rankin scale at 90 days, the median was 3 in the EVT alone group compared to 2 in the alteplase plus EVT group, which was not shown to be statistically significant. The chart below does show the distribution of scores on the modified Rankin scale. The majority of patients in both groups did have a score of 2, but there were more patients with scores of 5 and 6 included in the EVT group, likely contributing to the overall higher median score. For the secondary outcomes, when looking at the dichotomized modified Rankin scale scores, the results were also not statistically significant when scores were stratified in groups 0 to 1, 0 to 2, or 0 to 3. The median NIH Stroke Scale scores after 5 to 7 days was 4 in the EVT group alone versus 3 in the alteplase plus EVT group. Recannulization occurred in 2.8% of patients compared to 3.7 in the alteplase plus EVT group. And successful reperfusion on the last intracranial angiogram was seen in 78.7% compared to 83.1% in the alteplase plus EVT group. All of these, which were not statistically significant. For our safety endpoints, all of these were also not statistically significant. However, both deaths within 90 days and infarction in a new territory on imaging were higher in the EVT alone group. And so from all these results, ultimately what the authors concluded was that EVT alone was neither superior nor non-inferior to IV alteplase followed by EVT with regard to disability outcome at 90 days after stroke. So I think this overall trial was well-designed to assess the role of alteplase in addition to EVT in this patient population. Some of the strengths of this trial were that it did have similar patient populations as well as outcomes studied compared to the previous trials that looked at this clinical question. Modifying modified Rankin score for their primary outcome was appropriate and consistent with the literature. And another strength is that they did adjust the analysis for potential confounding factors. And what they did not adjust for, they did look in pre-specified subgroups. Some of the weaknesses of the trial, however, are the generalizability of the study. It was only conducted in European patients, which may not be applicable to all patient populations. And they did only look at patients who presented directly to an EVT-capable center. The treatment groups were also different in terms of rates of atrial fibrillation, age, and occlusion location, which could have confounded the results. Another weakness is that about 10% of the patients in the EVT group still did receive IV alteplase at some point during the trial, whether it be accidentally beforehand or as rescue therapy. The trial did not meet power, although it was only by one patient, and there was not a standardized technique utilized for EVT as both the use of stent retrievers as well as aspiration devices were included in the trial. So while the primary outcome was not statistically significant, it could be considered clinically significant. The median modified Rankin score was two in the alteplase plus EVT group, which is defined as slight disability, not requiring assistance. While the median was three in the EVT alone group, which is defined as moderate disability, requiring some help or assistance. So to some patients, the difference between not requiring assistance and requiring some help may be significant. In terms of risks associated with this treatment, the authors hypothesized a better safety profile with EVT alone. This was not demonstrated, however, as rates of intracranial hemorrhage were similar between the two groups, and mortality was actually slightly higher in the EVT group alone. There was, however, a high crossover rate with rescue alteplase, which may have contributed to these findings. But since none of the endpoints were shown to be statistically significant, and superiority nor non-inferiority was demonstrated, I don't believe there's enough data to support removing thrombolytic therapy at this time. So ultimately, what we can take away from this study is that while not statistically significant, alteplase followed by thrombectomy demonstrated lower modified Rankin scale scores at higher reperfusion rates than thrombectomy alone, showing that thrombolysis remains a viable strategy prior to mechanical thrombectomy in this particular patient population. There are also no differences in subgroup analyses noted, except for patients with atrial fibrillation who may favor combination treatment with alteplase and EVT, which could be a hypothesis generating for future studies. So when applying this study to clinical practice, it is important to consider that the data is still limited in non-Asian populations, with this being the only study being conducted outside of Asia. And this trial, along with previous trials, were conducted at centers capable of EVT, so the trial may not apply to patients who present to non-EVT centers. My current practice at my institution is to administer alteplase prior to EVT when patients qualify for both therapies, and based on the results of this trial, I don't foresee any major changes to our current practices. I do think further trials are needed in non-Asian populations to confirm the results of this trial and to see if there is a particular subset of patients that may benefit from withholding thrombolytic therapy. So this brings us to our second polling question. So based on these results, would you change your practice for patients who present and qualify for both alteplase thrombolytic therapy as well as EVT therapy? So it looks like the majority of us answered no, and I am in agreement with this. I think at the time, present time, we don't really have enough data to support removing thoromolytic therapy. It has been shown to be beneficial with combination therapy in prior studies. So I agree with the majority. 88% of us said no at this time. I think still more data is needed. And that is all I have for you. I would like to thank everyone who helped me prepare this presentation here at my institution, including my RPT as well as my preceptors. And with that, I will take any questions that anyone has. Thank you, Jill. I have a question for you. So you started the presentation reviewing some of the earlier literature, those studies that were conducted in Asia, I believe two in China and one in Japan. And in China, in the two studies, non-inferiority was actually reached for TPA with EBT versus EBT alone. Why do you think this trial did not have that same result? Do you think there was something different with the patients other than them being European and not in an Asian country? And any thoughts on that? Yeah, it's really difficult to say because overall, the patient populations that they utilized in the study were fairly similar, even in terms of baseline characteristics, compared to both of the previous trials that did show non-inferiority. So there's really not a clear one single factor that stands out on why they would have found non-inferiority from the patients in China. One thought was speculated that there was a higher or a lower rate of patients with atrial fibrillation included in this current study. So I'm not sure if that really had a significant impact on the results that they found or if it really was just due to a difference in patient population types. All right, seeing as though we don't have any other questions, we'll go ahead and conclude our session today. So thank you so much to our presenters today and the 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. Thank you so much.

critical care pharmacy

opioid administration

ICU opioid dose

opioid prescriptions

midodrine

vasopressor weaning

clinical outcomes

alternative patient populations

stroke treatment