Hello, and welcome to today's Journal Club Spotlight on Pharmacy webcast, which is supported by the Society of Critical Care Medicine CPP section. My name is April Finnegan, Trauma ICU Clinical Pharmacy Specialist at Inova Fairfax Medical Campus in Falls Church, Virginia. 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 session 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. You may also follow and participate in live discussion on Twitter following hashtag SCCM CPPJC and hashtag PharmICU. 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, 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 Cassidy Trainor, PGY-2 critical care resident at Yale New Haven Hospital in New Haven, Connecticut. Our second presenter is Alexa Jensee, PGY-2 critical care resident at UC Health Memorial Hospital in Colorado Springs, Colorado. And our third presenter is Michelle Lai, PGY-2 critical care resident at UC San Diego Health in San Diego, California. And now I'll turn things over to our first presenter. So, yeah, my name's Cassidy. And today I'll be presenting on the DO-RE-MI trial, or milrinone as compared with dobutamine for the treatment of cardiogenic shock. For some simple background, so cardiogenic shock is defined as ineffective cardiac output secondary to some insult, such as a decompensation of heart failure or acute myocardial infarction. And this causes clinical and laboratory signs of tissue hypoperfusion. Although not necessary for the diagnosis, you may see some hemodynamic abnormalities, such as a decreased blood pressure. You could have clinical criteria, such as decreased urine output or altered mental status that's indicative of tissue hypoperfusion, as well as some lab data showing organ hypoperfusion, such as increased CM creatinine. In thinking about the management of this disease state, management really revolves around cautious use of IV fluids, as well as mechanical support to increase cardiac output, vasopressor support to increase MAP, or your mean arterial pressure. And what we'll be speaking about today is inotropic therapy to increase cardiac output. The two agents we'll be discussing today are milrinone and dobutamine. They do have some distinct differences, such as their mechanism of action. Dobutamine being a beta receptor agonist, while milrinone prohibits the degradation of cyclic AMP to AMP. Their dosing is weight-based and falls within certain ranges. While milrinone should be dose-reduced for renal insufficiency, dobutamine does not have the same considerations. Their onset of action is pretty similar, however, milrinone does have a significantly longer half-life. In terms of their hemodynamic effects, both will increase cardiac index and inotropy, and they have a tendency to decrease systemic vascular resistance. However, dobutamine has a higher propensity to increase heart rate, whilst milrinone has a higher propensity to decrease systemic and pulmonary vascular resistance. Based on these effects, it's been postulated that dobutamine is more arrhythmogenic than milrinone, while milrinone has a higher incidence of hypotension than dobutamine. As there's not a lot of pragmatic data to guide our choice of inotropes in cardiogenic shock, we often base the choice on these hemodynamic effects, postulated adverse effects, as well as observational data and our personal experience. However, looking at the studies that do exist for these agents, they cannot be compared head-to-head based on different population studies, such as acute decompensated heart failure patients who are not necessarily in cardiogenic shock, heart transplant candidates, and there was a study conducted in 2019 in strictly cardiogenic shock patients. However, it should be noted, when comparing these patients to our study today, the patients in 2019 were less severely ill, with their cardiogenic shock being mostly secondary to surgery, as well as having higher ejection fractions of 55%. However, looking at the mortality rates, you can see that there's been no difference found between the two agents in any of the studies listed. This is the same for the primary clinical outcomes. The only significant difference found was there was an increased incidence of arrhythmias with dobutamine in the 2019 study. However, it should be noted that this was strictly due to an increase in sinus tachycardia and not necessarily arrhythmias of ventricular or atrial nature. Now, since the studies are so limited, what's the rationale for conducting doremi? So we know cardiogenic shock causes high rates of morbidity and mortality despite minor interventions. Inotropic therapy has shown to improve cardiac output and are an important backbone of therapy. However, our choice of inotropes is often based on observational data, theoretical mechanistic effects, and institutional practices. Thus, doremi sought to compare the efficacy and safety of milrinone and dobutamines in patients with cardiogenic shock in a pragmatic trial. Now let's jump into the trial itself. So this was a randomized controlled double-blind study that included adult patients with at least one indication for inotropic therapy. This could include diagnosis of shock with hemodynamic abnormalities and evidence of end-organ dysfunction, evidence of congestion despite intervention, or acute coronary syndrome complicated by shock with hemodynamic abnormalities. The main clinical exclusion criteria was presentation with out-of-hospital cardiac arrest. Now, these patients were randomized to receive either milrinone or dobutamine. And the doses remained blinded, and they did this by assigning each dosing range to different stages. The treating physicians and nurses were blinded to the agent as well as the numerical dose being given to the patients at all time and would titrate the doses based on which stage they wanted them to go to. To evaluate the outcomes of these interventions, they did a composite primary outcome of in-hospital mortality from any cause, cardiac arrest, receipt of transplant or mechanical support, myocardial infarction, incidence of stroke or transient ischemic tax, and then initiation of renal replacement therapy. Some of the other outcomes looked at were total time on inotrope, need for mechanical ventilation, change in hemodynamic parameters, presence of acute kidney injury, or presence of arrhythmia requiring intervention. They also went further with some of the safety outcomes, looking at incidence of sustained hypotension as well as need for antiarrhythmic or increased vasopressor therapy. To evaluate these outcomes, they did a power calculation that was an estimated of 55% of patients in the dobutamine group reaching the primary outcome. This was based on a meta-analysis the authors published in 2019 where they saw similar results. The alpha was set to 0.05 and beta to 0.2 for 80% power, predicting a 20% lower incidence of the primary outcome with milrinone. And this was also based on what they saw in their meta-analysis. They calculated they would need 192 patients to reach power. As far as statistical analyses, they used chi-square analysis and proportional hazards with log-rank testing to look at the composite primary outcome as well as mixed model for repeated measures to look at continuous variables that were collected multiple times throughout the trial and logistic regression model to look at ordinal variables. Now that we have all the methods set out, we can start looking at the results starting with the baseline characteristics. So overall, they were well-balanced between the two groups with the average age being about 70 years and almost 40% of the population being female. You can see that the average ejection fraction was 25%, which is reflective of most patients having either left ventricular or biventricular heart failure. While no p-values were reported and it's feasible to assume there was no significant difference between the groups for any characteristic, I did note that there was 11% more patients with myocardial infarction and previous PCI milrinone compared to dobutamine. The last thing I wanted to point out was this classification of cardiogenic shock. So this is a simplified classification denoting them as beginning, classic, deteriorating, or extremus. Most patients were in classic shock, which is they had hemodynamic signs as well as clinical signs of hypoperfusion. Deteriorating is all the same clinical criteria as classic, however, patients are now failing our interventions. And extremus are patients that are requiring mechanical ventilation, ECMO, and perhaps CPR. Before getting into the outcomes, I wanted to do a quick poll of the audience and see which inotrope is preferentially used to treat cardiogenic shocks within your institutions. So you can choose either milrinone, dobutamine, both are used interchangeably, or if you're unsure of the clinical practice at your institution. Okay, so according to the results, it seems like 24% used milrinone, 41% used dobutamine, and 32% said both agents are used interchangeably. I think that's kind of interesting, especially with this trial where they assumed much better outcomes with milrinone and they expected to be less arrhythmogenic. Let's go into the results and see how maybe people's opinions may change after that. So for the primary outcome, there was no significant difference found between the agents in terms of the composite outcome or the individual endpoints. They also did a time-to-event analysis and found that there was no significant difference still between the agents, nor was there any significant differences found when looking at pre-specified subgroups based on sex, age, affected ventricle, cause of dysfunction as well as severity, baseline renal dysfunction, or concomitant vasopressor use. Looking at our secondary outcomes, there was still no significant difference found in length of stay, receipt of mechanical ventilation, acute kidney injury, or normalization of lactate below two. Finally, and this may come as no surprise, but with our safety outcomes, there was no significant difference found in incidence of arrhythmia or sustained hypotension. In fact, every patient within the trial had some form of this hypotension. Now, this is contradictory to what we discussed earlier when looking at the hemodynamic effects of these agents and what we would expect that dobutamine had more arrhythmias while milrinone had more hypotension. And in fact, they did look at hemodynamic parameters throughout the trial and found that there was no significant difference at any time point. Something that may contribute to this is when looking at the doses used throughout the trial, especially at dobutamine, the most common doses were between 2.5 and 7.5 micrograms per kilogram per minute. When looking at literature, we see that dobutamine becomes more arrhythmogenic at higher doses, so those above 20 or even above 10 micrograms per kilogram per minute. The fact that the patients were on it for a shorter period of time at lower doses could contribute to the results that we see. But overall, the authors concluded that there was no significant advantage of milrinone over dobutamine in terms of efficacy or safety. When comparing this to the previous trials we looked at, we see that this is in line with there's no significant difference found with either mortality or clinical outcome. You'll see with our two trials in cardiogenic shock, there's quite a difference in the mortality rate. However, as I did previously mention, the patients in the 2019 study seem to be less acutely ill, and the cause of the cardiogenic shock differed from the one in the current study. So, evaluating the study, what are some of the strengths? This is the largest pragmatic trial for inotropes in cardiogenic shock, which is important because I said our studies are quite limited. Inclusion criteria was based on clinical assessment, whereas previous trials based their inclusion criteria on hemodynamic parameters. Using it on clinical assessment is more congruent with clinical practice and does lend to the external validity. The blinded dosing regimens allowed for this trial to remain randomized, and randomized groups were overall balanced in terms of their characteristics. Going forward, looking at some of the weaknesses, so only in-hospital outcomes were evaluated. If there's any difference in outcomes post-discharge, we would need further study to show this. There was a large delta value for the power calculation, so they expected there to be a 20% difference between the groups, which is quite large, and this left it underpowered to detect smaller but potentially significant differences in any of the outcomes. They did use a large composite outcome, including endpoints that they found clinically relevant and related to the use of inotropes. However, some of the outcomes, including incidence of stroke or TAA, have questionable relation to the use of inotrope or the difference between the two. And finally, the dose adjustments were determined by individual practitioners, which could lead to different treatments between the groups for different patients. And based on all of this, I wanted to re-poll everyone and how you feel when choosing inotropic therapy now. Would you continue to use the agent you originally picked, or is there another agent you would use, or do you feel more comfortable using them interchangeably? Wow, yeah, so 70% said they would feel comfortable using them interchangeably. And I agree. I mean, with this trial, we didn't see any difference in efficacy or safety. Of course, we would need further study for maybe specific subgroups, such as those who have cardiogenic shock secondary to acute myocardial infarction, or those at certain stages of shock. But I agree. Based on these results, I would feel comfortable using either agent. So finally, just getting to my takeaways from the trial. So as I just said, there are no proven differences in clinical outcomes between milrinone and dubutamine when used in this population. As of yet, I see no compelling need for institutions to change their usual practice with choice of inotrope. However, we would need larger studies to be conducted to detect these smaller magnitudes between group differences that may result. And with that, I'd like to thank you, everyone, for attending and allowing me to present, and I'll take any questions at this time. The study did mention that a good amount of patients 24 hours prior to randomization were on beta blockers. How do you think that may impact either the results, or did they mention what they did with that beta blocker therapy after randomization and inclusion into the trial? So it's actually interesting. Not long after publishing this study, they did publish a post hoc analysis looking at the beta blocker use. And they found that there was no significant difference with use of beta blocker for either agent and its effect on the outcome. One thing they did notice is that patients that were on beta blockers actually had a decreased incidence of mortality earlier in the study, within the first few days. So it is post hoc, so it's more hypothesis generating than anything else, but I don't think there was any difference seen with the beta blocker use. Thank you. We had one more question come through. How would you factor cost into your use of both agents for the same indication? Yeah, so milrinone is quite more expensive than dobutamine and there's actually been other studies looking at the economic cost difference and depending on how long the patient's there and how long they're on inotropes, the difference in cost can become quite large. So it's definitely a factor when you're thinking of we're allocating resources to a whole hospital. If safety and efficacy are both equal between the agents, choosing one like dobutamine where we may be able to reallocate these economic resources to other patients, I would definitely want to use dobutamine as long as it's the optimal agent for the patient. Okay, and one more came through. Just based on the pharmacology of both agents, was anything surprising to you about the results or is the results what you expected? So I think one thing is a lot of the previous studies focused on the hemodynamic parameters and changes in that and with those you see a lot of differences in terms of that milrinone causes more decreases in systemic and pulmonary vascular resistance while dobutamine causes higher heart rates. However, in most of the studies, they didn't find that there's a difference in arrhythmias except for the one where they were looking also at sinus tachycardia. So based on the hemodynamic parameters themselves, I am kind of surprised that there wasn't more hypotension with milrinone versus more arrhythmias with dobutamine. However, looking at the clinical outcomes from previous trials, I'm actually not that surprised that we didn't see anything overall clinically different between the groups. Awesome, looks like that's all the questions. So this concludes our Q&A session. Thank you, Kathy Trina. Before moving 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 the Spotlight on Pharmacy webcast. How many attendees are you viewing this webinar with? Just me, two to five people, five to 10 people, or greater than 10 people? Thank you. Now I'd like to introduce our second presenter, Alexa Jensey. All right, thank you so much for that introduction. I'm gonna be presenting on a 2021 trial from the Journal of Critical Care. It's the comparison of fixed dose versus Trina-4 titration of Cysatricurium in acute respiratory disease. So I'm gonna be presenting on a 2021 trial from the Journal of Critical Care. Cysatricurium in acute respiratory distress syndrome, or ARDS. So first off, we wanna go through why we paralyze in ARDS. This can increase the oxygenation, improve ventilator synchrony, and decrease oxygen consumption, and it can also decrease systemic inflammatory response, and this is through decreasing the inflammatory mediators of IL-6 and IL-8. Before I wanna move on, I wanna go through why we're using Cysatricurium instead of something like Rocuronium, and that's because it uses Hoffman elimination, so we don't have to adjust for any renal or hepatic adjustments for our patients. It also has a shorter half-life, and may have less risk of myopathy than the steroidal compounds like Rocuronium. The current guidelines, there are two of them. So the 2019 guidelines said that a paralytic agent should be considered in ARDS patients with a PaO2 to FiO2, or PF ratio, of less than 150 to reduce mortality, and this should be administered as a continuous infusion within 48 hours, but for no more than 48 hours. In 2016, Critical Care Meds said that a paralytic should be used as an IV infusion early in ARDS for patients with a P to F ratio of less than 150. They also say that Trenofor may be useful in incorporating into a more inclusive assessment of the patient, so they specifically recommend using Trenofor alone, but you can use it with other assessments of the patient to tritrate your paralytic. They also say you should use a consistent weight, like ideal body weight or adjusted body weight, instead of actual weight and obesity for the dosing of paralytics. So two main trials, we have the ACQUIRISIS and the ROSE trial. Both of these use the Satrokerium as a 15 milligram bolus, followed by a 37.5 milligram per hour continuous infusion. However, the ACQUIRISIS trial used this versus placebo, so both of them had deep sedation, whereas ROSE uses usual care as their comparison, and this is because by this time, they had found that lighter sedation may be beneficial in these patients, and both of them gave the medication for 48 hours. The population in ACQUIRISIS was defined as severe ARDS of a PF ratio of less than 150, and a PEEP of more than or equal to five with bilateral pulmonary infiltrates consistent with edema, whereas ROSE defines this as a moderate to severe ARDS with a PF to F ratio of less than 150 as well, so just a little bit different verbiage here, and a bilateral pulmonary opacities as well in this trial. The findings of ACQUIRISIS showed that the hazard ratio at 90 days was 0.68, and the 28-day mortality was 23.7% in Cysastrocurium versus 33.3% in placebo, so both of these were statistically significant showing benefit in the paralyzed patients. However, the ROSE trial was stopped early due to futility and showed that the 90-day mortality of 42.5% in Cysastrocurium versus 42.8% in the control group was no different. Another background study we will go through is the TRANO4 ARDS study from 2017, and this was a prospective open-label trial that compared TRANO4 dosing to what patients would have received with continuous dosing like in the ACQUIRISIS trial. This population was moderate to severe ARDS, which they defined as a P to F ratio of less than 120 and a PEEP of five, and they also had to be in the MICU and requiring continuous administration of Cysastrocurium. They received this as a 0.2 milligram per kilogram bolus, and they started continuous infusion starting at 0.18 milligrams per kilogram per hour, and this was titrated to a goal of zero out of four twitches and all patients were maintained at the Richmond agitation scale of less than negative four, so they were adequately sedated, and their findings were that the mean initial dose was 11.8 milligrams per hour and the final dose was 14 milligrams per hour. These were both significantly lower than the doses that these patients would have received if they were included in the ACQUIRISIS as well as the ROSE trial, which was 37.4.5 milligrams per hour. Their overall consumption in the study group was 700 milligrams compared to over 2,000 in the patients who had received the ACQUIRISIS dosage. This was also significantly less, and they also found that they reduced costs by about 70 euros per patient because this was done in France and this translates to about $83 per patient, US dollars. This trial's hypothesis was that in patients receiving continuous infusions with Atrocurium for the treatment of ARDS, there will be differences in the ventilator and clinical outcomes between patients receiving fixed dose versus titratable regimens. Methods of this trial was a single center retrospective cohort study, and this was done at the University of Kentucky Chandler Medical Center. This is a center that has 865 beds and is a tertiary referral center, and this was done from 2017 to 2018. This was pre-COVID, so keep that in mind. The two groups were the fixed dose group and the titratable group. Fixed dose received non-titratable 37.5 milligrams per hour dosing, and this was the same as they used in the previous trial. Titrated dose was titrated to a train of four of one to two twitches out of four, and they did not specify a duration or a starting dose, so keep that in mind as well. The inclusion criteria were any adult admitted to the MICU that received a continuous infusion of Fibatricurium for over 12 hours for the treatment of ARDS. They were excluded if they received both strategies for more than 12 hours each. If they received both strategies and one was less than 12 hours, that was called the non-dominant strategy, and the patient was then placed in the dominant strategies group for analysis. Continuous infusion of a paralytic prior to admission would exclude them, as well as receipt of a paralytic for any indication other than ARDS, and a P to F ratio of more than 300. So, I started out looking at 197 patients who were in the MICU receiving Fibatricurium for at least 12 hours. 13 were excluded for alternative indication. One patient was pregnant. Seven were paralyzed on admission. Five received the non-dominant strategy for more than 12 hours, and four had a P to F ratio of over 300. So, 167 total were included. 126 went into the titratable group, and 41 into the fixed-dose group. Their primary outcome was the P to F ratio in relation to baseline, and this was assessed at 24 and 48 hours following Fibatricurium initiation. They also looked at time to initiation or discontinuation to extubation, ventilator-free days of up to 28 days, average dose of the drug administered in 48 hours, requirement of additional boluses, re-initiation of the paralytic, ICU length of stay, and mortality. And a P value of less than 0.05 was considered statistically significant in this trial. So, some baseline characteristics we'll go through. Their average age was about 50. They were pretty evenly split between male and female, and their weight was about 90 kilograms in both groups. They also used the Alex Hauser Comorbidity Index, and this categorizes 30 comorbidities and produces a score that's associated with death, and it ranges from negative 19 to a positive 89, so they're right in the average range. They're of a score of seven, and this is similar to the Charleston Index, but that only categorizes 17 comorbidities, where this one uses 30. The duration of mechanical ventilation prior to Cysatricurium was 0.7 days in both groups. The CILFIS scores in the titrated group was nine, and the fixed dose was an average of 11. This was a statistically significant difference, but this could have been due to the retrospective nature of the study where the provider chose which group the patient fell into. Boluses of the paralytic prior to continuous infusion was seen in 50 to 60% in both groups, and the P to F ratio prior to Cysatricurium was 96 in the titrated group and 97 in the fixed dose group, so most patients did fall into our severe ARDS care and our characteristics. The net fluid balance I included because the conservative strategy we've seen could be more beneficial in these patients. So in the titrated group, they were on average 2.5 liters positive. When the fixed dose, they were about 1.7 liters positive. So their main outcomes, their primary outcome was the P to F ratio at 24 hours following initiation. This was not statistically different between the titrated and fixed dose group, but we do see a increase from their baseline characteristics where we saw that in the high 90s was their original P to F ratio, and now we've moved into the 140s. If we look at the P to F ratio at 48 hours, it's not much different than between the 24 hours, but it is still much higher than they started in the baseline characteristics. The duration of the infusion was 47 hours in the titrated group and 48 hours in the fixed dose group. And this is in line with all those previous studies that we talked about earlier. The average dose in micrograms per kilo per minute was two in the titrated group and 6.4 in the fixed dose group. This was a statistically significant difference, and we saw about a three times higher dosage rate in the fixed dose group than our titrated group. The bolus parasolytic prior to continuous infusion was seen in 66.7% of titrated group and in the other group. Re-initiation was seen in 50% of both of them, and then fluid administration with cytosaccharin at the bottom here. So this is for a hypothetical patient who weighs about 70 kilos. They would have administered 504 milliliters to this patient throughout 48 hours with a concentration of 0.8 milligrams per milliliter. In the fixed dose group, they would have administered over 2,000 milliliters to a patient in that 48 hours. So we see quite a difference there. Some other outcomes they included was initiation to extubation in days, and this was about six days in both groups. And then cessation of our paralytic to extubation was about four days in each group. Then we had ventilator-free days within 28 days with zero in both groups. So they did not have any ventilator-free days in them. And then ICU length of stay was 11 days in titrated, whereas 9.2 in the fixed dose group, and mortality was about 40 to 50% in both groups. The author's conclusion was that in the treatment of ARDS, ventilator and clinical outcomes were no different between patients that received fixed doses of tachycurium versus Trano-4. To some strengths of this study, this was a real-world use of the tachycurium because it was a retrospective study, and the fixed dose was equivalent to the doses we saw in the QRISIS and the ROSE trial, which is good. However, there are some limitations. It is a small single-center retrospective design that may limit the external validity, and that can limit our generalizability to other institutions. Physicians also chose the Trano-4 versus fixed dosing strategies. This could lead to some selection bias and could be why we saw the difference in SOFA scores in the baseline characteristics. Trano-4 can also have inter-rater variability, so between different nurses or different providers that are doing the testing, they could get different scores and different titration from that. There was also no assessment of fluid balance after administration of the study drug and no details on prone positioning either. So my conclusion and kind of the takeaways from this trial is that fixed dosing and titrated strategy for dosing cis-tachycurium was associated with similar ventilatory and clinical outcomes. However, the titrated strategy was associated with lower doses and about three times less. This could lead to average volumes administered being smaller as well, which could be very helpful in our ARDS patients. And also keep in mind that the statistically significant outcome was a secondary outcome, and our primary outcomes were all non-significant. These are hypothesis-generating, but we can take some clinical usefulness out of these outcomes. So I have two polling questions. The first one is going to be what type of dosing are you using for ARDS patients who are currently paralyzed? Is that going to be the titration using Trenofluorobispectral index, fixed dose, or titrated based on ventilator dyssynchrony? Okay, so I see most people are using the titration based on Trenofluorobispectral index, and we also here at UCHealth use the titration based on Trenofluorobispectral index. That doesn't surprise me. Okay, and the second question is, which neuromuscular blocking agent and strategy does your institution use? Are you using ZEK boluses as needed or as a continuous infusion, Cysatricurium boluses as needed or as a continuous infusion, or a combination of these strategies? Okay, and again, I see that the main response here is Cysatricurium continuous infusion, and that is also what we use here, and it's titrated based on the TRANO4 as I talked about earlier. All right. Thank you all very much for attending my presentation. At this time, I would like to open up the floor to any questions you may have for me. Thank you, Alexa. The first question is, it appears that most studies focus on cis-atricurium. Would you extrapolate the findings of this study to other neuromuscular blocking agents such as atricurium, vecuronium, and rocuronium? Yeah, that's a very good question. I think that because of the differences between cis-atricurium and rocuronium and vecuronium, I don't think that we can extrapolate to different paralytic agents. I think it would be interesting for further studies to take a look at that to see if that would be the same outcomes that we're seeing, but I don't think at this time we can necessarily extrapolate to others. Can you comment on the use of bolus dosing? In this study, I think greater than 50% received bolus dosing. Is that your practice to use cis-atricurium boluses prior to the infusion? Yeah. In this trial, they had the option of whether or not they wanted to use a bolus before they started the continuous infusion. Here, we have an order set that also gives them an option that will add a bolus dose. The bolus dosing options here are the 0.05 mg per kg or 0.15 mg per kg, and then you can go into a continuous infusion where the provider can choose the starting dose. We, like this trial, have an option to include a bolus, but it's not required. In line with that, based on this study, what dosing strategy would you recommend? Based on this study, I would recommend dosing based on Trana4, but also in combination with ventilator dyssynchrony. Like the guidelines before said, Trana4 shouldn't be used alone. We should also keep in mind the patient and look at the patient in the room and see how they're doing. If they're not having any ventilator dyssynchrony and they have maybe three out of four twitches instead of two, I think that's okay, but the Trana4 dosing based on the patient and their Trana4 would be helpful. I think it depends on the patient whether or not to include a bolus dose. Some may need it and some may not. Is there a role for bolus dosing PRN rather than continuous infusion? Yeah, there could be a role for bolus dosing, both in combination with the continuous infusion as well as on its own. We do use Zika boluses if a patient is not on a Cysatricurium drip on occasion, if they have ventilator dyssynchrony, just as a PRN every few hours on the MAR for the patient. There could be a role for just doing the PRN doses of either Vacuronium or Cysatricurium, whatever the institution uses. What objective parameter did they use for vent dyssynchrony? So, in this trial, they did not specify exactly what they used as vent dyssynchrony, and they also didn't include how many mid-infusion boluses that they used. They only spoke on whether or not they used an initial bolus, but didn't touch on whether or not they had vent dyssynchrony afterwards. And for the last question, this is more of an operational question, but are nurses allowed to push PRN boluses of paralytics at your institution that you know of? So, it's situation-dependent. If they have an order on the MAR and it's clinically appropriate for the patient, such as they're intubated, et cetera, then yes, they can do the PRN boluses when it's needed in the ICU. Thank you, Alexa. That concludes our Q&A session. Now, I'd like to introduce our final presenter, Michelle Lai. Hi, everyone. Thank you for having me here today. My name is Michelle Lai. I'm a PGY-2 critical care resident here at UC San Diego Health, and the title of the article I'll be discussing today is low-dose versus standard-dose four-factor prothrombin complex concentrate, or four-factor PCC, four-factor 10A inhibitor reversal, and spontaneous and traumatic intracranial hemorrhage. So first, I'd like to start off with a polling question. At your institution, what's the recommended dose for four-factor PCC for factor Xa inhibitor reversal in ICH? Oh, 47% chose B. Okay, so most, I guess the highest answer was 50 units per kilo. All right, let's move on to the presentation. So, the 2016 Neurocritical Care Society guidelines recommend 50 units per kilo of four-factor PCC if ICH occurred within 3-5 terminal half-lives of factor Xa inhibitor exposure or in the context of liver failure. However, recent studies suggest that 25 units per kilo of four-factor PCC may be similar to 50 units per kilo for factor Xa inhibitor reversal in ICH. So, the research question of the study was, what's the difference in hemostatic efficacy of 25 units per kilo versus 50 units per kilo of four-factor PCC for factor Xa inhibitor reversal in ICH? This was a multi-center retrospective cohort study within one academic medical center and four community hospitals in Central Texas. Examinations were included if they were at least 18 years of age and they received 25 units per kilo or 50 units per kilo of four-factor PCC for factor Xa inhibitor reversal in spontaneous or traumatic ICH, and they had to have apixaban, rivaroxaban, or adoxaban on their medication list. They were excluded if they didn't have a follow-up CT or MRI scan or it was completed greater than 48 hours after initial scan, and they were also excluded if they received a massive transfusion protocol. The primary outcome measured was hemostatic efficacy, which was defined as a hematoma volume showing no change, less than or equal to 35 percent change, or an improvement on repeat CT or MRI scan versus initial scan, and this was based off of a definition recommended by the International Society of Thrombosis and Hemostasis, and the secondary outcomes were in-hospital mortality, length of stay, thrombotic events, including the ones listed here, and thrombotic events, it wasn't specified the timing of these events, unfortunately, and then lastly, the need for surgery or additional blood products, which also included four-factor PCC. For statistical analysis, an 80 percent hemostatic efficacy rate was assumed based on previous studies in which there was a 70 to 90 percent efficacy rate, and for the sample size calculation, it was as follows, to detect a 10 percent difference in the primary outcome between groups, a sample size of 276 patients total would be needed to achieve 80 percent power. And here are the baseline demographics, so age and height were similar between the 25 units per kilo and 50 units per kilo groups, however, the weight was higher in the 25 units per kilo group compared to the 50 units per kilo group. There were more males in the 25 units per kilo group compared to the 15 units per kilo group, however, this wasn't statistically significant. A varoxaban was more common in the 25 units per kilo group, whereas apixaban was more common in the 50 units per kilo group. And for factor Xa inhibitor timing assessment, most patients didn't have this assessed, however, among the patients that did have the factor Xa inhibitor timing assessed, it was longer in the 25 units per kilo group compared to the 50 units per kilo group. And lastly, for timing of follow-up scan, these were similar between groups, and most patients had a follow-up scan within 12 hours. The primary outcome of hemostatic efficacy was achieved in 82.3 percent of the 25 units per kilo group versus 83.9 percent of the 50 units per kilo group, so there was no statistical significant difference. For secondary outcomes, there was no statistical difference in in-hospital mortality, length of stay, thrombotic events, need for surgery, and need for additional blood products. Of note for the safety outcomes thrombotic events, there were only three events total in the study, and all three events actually occurred in the lower 25 units per kilo dose group. So the author's conclusion from the study were that for the reversal of factor Xa inhibitors in ICH, a 25 units per kilo dose may be an effective alternative to 50 units per kilo four-factor PCC dosing. For the population, strengths of the study were that it had broad inclusion criteria, so it included various bleed locations, various bleed types, so spontaneous and traumatic. The exclusion criteria were appropriate. They excluded patients who received the massive transfusion protocol and didn't have the follow-up scans. Another strength was that there was a similar time to follow-up CT or MRI scans between the two groups, so potentially minimizing that as a confounder. Some limitations of this study were that the sizes of bleeds were not reported, so we didn't have a baseline or actually follow-up hematoma volume reported, so it's unclear whether one group had more severe bleeds at baseline or not. Additionally, only 29% of patients had documented time of last factor Xa inhibitor dose, so it's unclear whether four-factor PCC was warranted in the first place. For example, if a patient received their last dose of epixazepam seven days ago, they probably didn't need four-factor PCC, but we weren't able to assess this. The differences in baseline demographics weren't discussed, so we mentioned earlier the 25 units per kilo group had a higher weight compared to the 50 units per kilo group, so leading to a smaller absolute difference in total four-factor PCC dose. Additionally, the 25 units per kilo group had a longer time to last factor Xa inhibitor dose compared to 50 units per kilo group, so there could be some prescriber bias there in choosing the different doses for these patients. Additionally, they didn't measure the baseline functional status, so it's difficult to tell which group had more severe or whether they were the same functional status. And for the intervention, a strength of the study is that it compares 25 units per kilo and 50 units per kilo four-factor PCC dosing in ICH, whereas most previous studies only looked at one or the other. However, some limitations, or a very big limitation, is that the dosing of four-factor PCC was at the discretion of the provider, and this is due to the retrospective nature of this study. So, like we mentioned before, we don't have the baseline bleed reported, and there's differences in the time to last factor Xa inhibitor dose, so those could all have led to major prescriber bias for choosing which dose to use. And then lastly, the rounding of the doses were unclear, so if patients fell in between the 25 units per kilo and 50 units per kilo group, it didn't really specify how they were categorized and what the cutoffs were, and this study didn't really mention rounding the doses off for, like, a max dose. For example, from the Warfarin reversal dosing suggestions, there is a max cutoff for 2,500 units for 25 units per kilo dosing and a max for 5,000 units for 50 units per kilo dosing, but this wasn't mentioned in the study. And for the endpoints, the strength of the study was that the definition of hemostatic efficacy was consistent with previous literature, so the 35% cutoff for hematoma expansion volume was consistent with previous studies on four-factor PCC dosing, and actually, the Ndexonin alpha trial also uses 35% cutoff for hematoma volume. Additionally, the secondary endpoints assessed potential confounders, such as need for surgery and need for additional blood products, so it was good that they did that. However, the limitations were that the primary outcome, although consistent with previous literature, is measuring a hematoma volume change, and that's a surrogate endpoint, so does it really matter whether the hematoma volume stayed the same or improved if the functional status declined in these patients? And for statistics, although power was not met in the study, they did calculate the number of patients needed to detect a 1.3% difference in primary outcome, and they calculated that to be 17,000 patients needed to achieve power, which they mentioned admittedly was not feasible in a retrospective study like this. So overall, my takeaway points, first, I can't mention a factor Xa inhibitor reversal without mentioning the first and only FDA-approved product for this indication, which is not four-factor PCC, but is actually Ndexonin alpha, which is why it's on this slide. But firstly, safety. For the four-factor PCC, 25 units per kilo versus 50 units per kilo doses, there was no statistical difference in thrombotic events, and we actually mentioned that all the thrombotic events occurred in the 25 units per kilo group in this study, compared to the Ndexonin alpha, in which there were about 10% of the patients had thrombotic events within 30 days in the study that led to its approval. And for efficacy, between the 25 units per kilo versus 50 units per kilo, the efficacy was similar, as rated by the hemostatic efficacy, and then there are several caveats. As I mentioned earlier, there was an unknown size of bleeds, and the big limitation was that there is a discretionary four-factor PCC dosing. There could be a lot of prescriber bias based on the size of the bleeds, last known factor 10A inhibitor dose, whether they're going to get surgery or not. So those are all major factors that could have led to the different doses, and then differences in baseline demographics. And for Ndexonin alpha, this also measured good hemostasis, excellent or good hemostasis based on the 35% cutoff for hematoma expansion volume, and this was similar compared to the four-factor PCC, and this was achieved in 82% of the patients. And knowing that safety and efficacy are similar between the four-factor PCC doses, the next thing I'm looking at is cost. So of course, the higher the dose, the more drug we're using, the higher the cost. And then compared to Ndexonin alpha, there's about a five to tenfold higher cost of Ndexonin alpha compared to four-factor PCC. So overall, my conclusion is that 25 units per kilo of four-factor PCC is a reasonable alternative to 15 units per kilo four-factor 10A inhibitor reversal in ICH. Again, similar safety, similar efficacy, and then lower cost would make 25 units per kilo an attractive option for four-factor PCC dosing. And I'd like to acknowledge my preceptors, Dr. Craig Stevens and Dr. Katie Derry for all of your guidance and running through this journal club with me multiple times. And here are my references, and this is my final polling question. So if your institution uses weight-based dosing of four-factor PCC for factor 10A inhibitor reversal in ICH, is there a maximum dose? So, like the first polling question, it looks like most of your institutions use the 50 units per kilo dosing with a max of 5,000 units. All right, thank you so much, and I'd like to open it up to any questions. Thank you, Michelle. The first question for you, was there a difference in the baseline antiplatelet therapy prior to admission between both arms, and would that influence your results? Yeah, that's a great question. Let me pull it up. So, I don't believe they really specified the baseline antiplatelet therapy, but I'd have to double-check. Okay, we can move on to the next question. Based on this study and your analysis of indexinant alpha, would you recommend indexinant alpha or four-factor PCC? So, based on this study, due to its similar, I guess, efficacy that we're talking about using the hemostatic volume expansion percentage cutoff of 35%, it was very similar between the groups. So, it was 82% in the indexinant alpha study versus 82% to 84% in this study as well. So, similar efficacy there, and it seems to have better safety in four-factor PCC with lower rates of thrombotic events. So, just based on those two aspects, I would favor using four-factor PCC. And lastly, there's the added benefit that four-factor PCC has a lower cost than indexinant alpha. So, I'd still favor four-factor PCC. Okay, it looks like they allowed some re-dosing in the study, possibly, for four-factor PCC. So, at what point would you decide to re-dose four-factor PCC for those who initially received 25 per gig? I guess, based on the follow-up imaging, if there's an expansion, I would consider re-dosing and then also if there's worsening clinical status, but again, it's difficult to tell in this study because there wasn't a measure of, like, functional status at all. Did the authors discuss the differences in thrombotic events between the two-dosing strategies, having the higher incidence of events in the lower-dosing arm? Yeah, they didn't mention a reason for it because it's pretty counterintuitive that the lower-dose would have more thrombotic events, so they did mention, like, the type of events and that it may have been also due to holding their anticoagulation. For example, all three patients who did have the thrombotic events had their anticoagulation held up until the point of their thrombotic event. For some of them, it was like two weeks after receiving four-factor PCC, so there wasn't really an explanation why the lower-dose would have more thrombotic events, especially since it's pretty counterintuitive, but they did just, like, the list of events that did occur. And you mentioned that the 25 units per gig may be a reasonable alternative, but would you change your protocol based on these results? Actually, our institution does use the 25 units per kilo dosing based on this study and other previous studies that had patients achieve hemostatic efficacy. So I guess I can't speak to my institution, but if I were at an institution who's already using 50 units per kilo dosing, I would consider switching to the 25 units per kilo, even based on these results. Thank you for that. Thanks, Michelle. This concludes our Q&A session. Thank you 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 concludes our presentation today.

inotropic agents

cardiogenic shock

cystic fibrosis curium

acute respiratory distress syndrome

fixed-dose dosing

train-of-four monitoring

factor Xa inhibitors

intracranial hemorrhage

hemostatic efficacy