Hello, and welcome to today's Journal Club Spotlight on Pharmacy webcast, which is supported by the Society of Critical Care Medicine's CPP section. My name is Christina Larrizade. I'm a clinical pharmacy specialist in the cardiovascular ICU at Holmes Regional Medical Center in Melbourne, Florida, and 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. So, thank you for joining us. A few housekeeping items before we get started. There will be a Q&A after each of today's speakers. To submit questions throughout the presentation, type into the question box located on your control panel. You will also have the opportunity to participate in several interactive polls. When you see a poll, simply click the bubble next to your choice. You may also follow and participate in live discussion on Twitter following hashtag sccmcppjc and hashtag PharmICU. Please note the disclaimer stating that the content to follow is for educational purposes only. 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 Dr. Michaela Warfield, a PGY-2 critical care pharmacy resident at Mayo Clinic in Rochester, Rochester, Minnesota. She will present on retoplase versus alteplase for acute ischemic stroke. Our second presenter is Dr. Marissa Marks, a PGY-2 critical care pharmacy resident at the Johns Hopkins Hospital in Baltimore, Maryland. She will present on early selexicab use and spontaneous intracerebral hemorrhage is associated with reduced mortality. And our third presenter is Dr. Zivia Gutman, a PGY-2 critical care pharmacy resident at SBH Healthy System in Bronx, New York. She will present neuromuscular blocking agents during targeted temperature management for out-of-hospital cardiac arrest patients. And now, I'll turn things over to our first presenter, Dr. Michaela Warfield. Thank you for the introduction. My name is Michaela, and I will be presenting on the RAISE trial, retoplase versus alteplase for acute ischemic stroke. Stroke is a very important topic just because we have about 800,000 patients on an annual basis that present with a stroke in the United States. About 87% of these are ischemic strokes, and according to the CDC, this is the number one cause of long-term disability. Putting this into a timing perspective, this means that every 40 seconds, somebody in the United States has a stroke, and every 3 minutes and 14 seconds, somebody passes away as a result. That means that throughout the duration of this presentation, approximately 23 people will have a stroke in the United States. Pharmacological treatment is composed of two different options. First, we have TPA, which is tissue plasminogen activators, and we also have mechanical thrombectomy. TPA agents include alteplase, tenecteplase, and also potentially retoplase. These work by binding with plasminogen to create plasmin and then breaks down the fibrin in a clot that would be present in an acute ischemic stroke. Looking at our agents that we know of historically, we have alteplase and tenecteplase. With alteplase, there's a few advantages and disadvantages, with advantages being that it is the one that is approved by the FDA for a treatment of acute ischemic stroke, and we do have a lot more historical literature to support its use. We have seen that there is efficacy with using it for acute ischemic stroke. However, some disadvantages include that it does require a bolus dose as well as an infusion given over one hour. It also might pose a higher risk for bleeding compared to tenecteplase, and it is a bit more expensive. When looking at tenecteplase, this has a higher fibrin specificity, making it potentially more advantageous over alteplase. It also has a longer plasma half-life, which means that it might help break down the clot for a longer duration when compared to alteplase. It is easier to administer just because it is a single bolus approach, and it has been shown to be non-inferior to alteplase. However, when we utilize it, it is technically off-label use for acute ischemic stroke, and it is a little bit newer, so there is limited data. However, it has been shown to be non-inferior, and at this time, there is debatable question of whether it is superior to alteplase. When we look at retoplase, this is also genetically modified, and it is approved for the acute treatment of myocardial infarction, so it has been on the market for quite some time since the 1990s when it was approved for acute MI. However, we have limited data available for its use in ischemic stroke. It works by activating plasminogen directly, and this includes increased fibrinogen depletion and higher clot dissolution. When we compare it to our other agents, it does have a longer half-life than alteplase, making it potentially advantageous, and it does have weaker binding with fibrin, allowing for more free diffusion through the clot. You might say, well, this seems a little bit contradictory when we looked at tenecteplase when we liked the fibrin specificity, so there is a lot more literature and data that needs to be included on how these agents work to then determine which one is a little bit more advantageous based on the mechanism. It also poses potentially a higher risk of breeding because of the specificity differences. When comparing to tenecteplase, it has enhanced conversion of plasminogen to plasmin, whereas tenecteplase is more of that fibrin specificity that I alluded to. There is historical literature for its use. However, both of these trials were specifically in acute MI rather than acute ischemic stroke. Our first trial, the RAPID-2 trial, was done comparing retoplase to alteplase, and we saw that there was an increased rate of early reperfusion and did not have any differences in unsatisfactory outcomes, which included death, reinfarction, shock, EF of less than 40%, and more. In the GUSTO-3 trial, this was similar, and it was retoplase versus alteplase in acute MI, and we saw that there were no differences in survival benefit, the intracerebral hemorrhage incidence, or death or non-fataling disabling stroke, which goes to show that we don't necessarily know that it's better than alteplase, but it didn't necessarily have worse outcomes, hence why it is approved for the use of acute MI. Before we jump into our trial, I do want to review just a little bit of background on how we define stroke severity and what kind of scoring tools we have. The first is the NIHSS, and this is, this scores on 13 different categories ranging from 0 to 3 for each score, and then this is added for a cumulative score anywhere from 0 to 42. I really just want to draw your attention to the mild and moderate, because this is where many of our patients in the RAISE trial will fall in their severity of their stroke, so mild being anywhere from a score to 0 to 4, and moderate being a score of 5 to 15. We also have the Modified Rankin Scale, and this is essentially a degree of disability after somebody presents with a stroke, and so this is how we can determine whether their functional status is improved after administration of medications or after we treat their stroke, and therefore they can range anywhere from 0, which is no disability, all the way up to 6, which is no disability, and then finally, a severe disability, and this is what our outcome will be looking at within the RAISE trial today. Jumping into the trial, the RAISE trial was a phase 3, multi-center, non-inferiority, randomized trial. They did have a nested superiority as well, which we'll get into later. They looked at comparing retoplase, which was given as a two-bolus approach compared to alteplase with respect to the functional outcomes after they were treated for their acute ischemic stroke. This trial specifically included patients from ages 18 all the way up to 80, and they had to have a disabling ischemic stroke, which they defined as an NIHSS of 4 to 25. They had to present within the window that we would typically give thrombolytics, and really at baseline, this is what's important, is that they had an excellent functional status, which they defined as a Modified Rankin Score of 0 or 1. They did exclude any patients that had a previous or planned thrombectomy, and of course, any contraindication to the medications that they were administering. Looking at our baseline characteristics, we can see that majority of the patients in this trial were male, with about 70% of patients, and all of these patients were from the Asian race. When looking at their stroke severity at baseline, when they were admitted, the median NIHSS was 6 in both groups, so this falls into that mild to moderate range, with majority of patients falling in that moderate range from 5 to 15, and their Modified Rankin Score, with most patients being a 0 before their index stroke. They were administered medications at a median time of about 180 minutes after symptom onset, and yes, I do know the numbers here look like they're a mistake at the bottom, but the distribution for what time patients were given the medication, it was the exact same in both groups, with about 50% being within three hours, and 50% being above that three hours. Patients, the 1,400 patients were randomized in a one-to-one fashion, with 707 receiving IV retaplase, which was given as that two bolus approach, which I alluded to earlier, so there were two 18 milligram boluses, and these are given 30 minutes apart. With alteplase, this was done, as we've seen in many of our previous trials, so this is a weight-based infusion, 10% of which is given as a bolus, and the remainder given over an infusion over one hour. All other treatments were guideline-based, and they followed standard practice for acute ischemic stroke. Looking at our outcomes, the primary outcome that they looked at in this trial was excellent functional status at 90 days. This was defined as a Modified Rankin Score of 0 to 1, and we can see here, based on the p-values, retaplase was seen to be non-inferior to alteplase, and with the nested superiority, they also found that it was superior to alteplase. We can see the breakdown of the Modified Rankin Scores at 90 days. Down here, with the distribution, you can see that retaplase overall had lower Modified Rankin Scores when comparing to alteplase, meaning that they had less of that disability after they were given the medication, when they were assessed at that 90-day mark. With our secondary outcomes, they also looked at good functional status, and this was defined as a Modified Rankin Score of 0 to 2. We also had the Medium Modified Rankin Score, as well as Early Dramatic Recovery, which they defined as a decrease of greater than or equal to 4 points on the NIHSS score, or a score of less than or equal to 1. They assessed this both at 24 hours, as well as 7 days, and they did the Barthdel Index Score at 90 days as well, which is essentially a patient's ability to perform their normal daily activities. All of these outcomes were non-inferior, with the exception of that Medium Modified Rankin Score at 90 days, with a tendency for retaplase to be non-inferior with a little bit better outcomes. Our safety outcomes are also very important to assess with these medications. So, the safety outcomes that they ended up looking at were the symptomatic intracranial hemorrhage within 36 hours, because they had to get subsequent imaging. They also looked at intracranial hemorrhage at 90 days, non-massive hemorrhage at 90 days, which included anybody that required prolonged hospitalization as a result, if they had additional imaging, compression, hemostasis, surgery, or required discontinuation of the study drug. And they also looked at all-cause death at 90 days. We can see that none of these differences were statistically different, with the exception of that non-massive hemorrhage at 90 days. They did not report out which of these outcomes that were included in the non-massive hemorrhage was really guiding that difference, so it's hard to draw any conclusion specifically from that, but we can say that there was an increase in non-massive hemorrhage at 90 days with the use of retaplase compared to alteplase. Wanting to look at some of the strengths and limitations on how to interpret this study, the strengths included that they did have a very well-balanced baseline groups, and I think this is important, just because then we know that there's homogeneity amongst both groups. They also had minimal exclusion criteria. Really, the only notable one was excluding those who had a planned or previous thrombectomy. And then the limitations, which I already kind of alluded to earlier, but the low-median NIHSS at baseline across both groups just makes it a little bit challenging to interpret this and apply it to patients that might present with a more severe stroke. We also only included Asian populations in this study, again, making it a little bit hard to extrapolate to other populations, just because this might not be the patient population that we see in our institutions here in the United States. And they also used an open-label design, and they also used an open-label design, just opening up any possible bias there, because they were unable to keep it blinded for the reason being the differences in administration with alteplase and retaplase. What we can really draw from this, so the conclusion being that the use of retaplase compared to alteplase at that 90-day mark did lead to excellent functional status, a better excellent functional status with the use of retaplace over alteplase, but there also was an increase in the non-massive hemorrhage that was seen in this patient group. So you might ask, what do we actually do with this information, and what are the takeaways that we can draw from this? I think there are a few questions that remain to be answered with the use of retaplace, the first one being that they didn't compare retaplace to tenecteplase. Given at my institution, we do lean a little bit more on tenecteplase, I think it's a little bit hard to interpret whether we should be utilizing retaplace at this moment for acute ischemic stroke, just because we don't have any literature comparing retaplace specifically to tenecteplase, only to alteplase at this time. We also don't necessarily know the optimal dosing and administration, because this was a phase 3 trial, they previously looked at 12 milligram boluses, whereas this one used 18 milligram, they did see that there were better outcomes with the 18 milligram without increasing the risk of hemorrhage, but we don't necessarily know that that is the best dose at this time, so there's further literature that might be warranted looking at what dose we should be utilizing, and whether the two bolus approach is necessary or not. We also need to look at potentially what this might look like if we included patients with a higher median NIHSS. I think a lot of patients that come in might come in with a higher NIH, and this is hard to know whether we should be using retaplace at this time, given that with the median being six for this patient group, I think it's hard necessarily to interpret, yes, if they're getting thrombectomy for one, or if they come in with a higher NIH, should we be utilizing retaplace? At this time, we don't necessarily know, and I wouldn't necessarily feel comfortable doing that, just because of the data that we have available. And again, like I mentioned earlier, with our patient population being included only Asian populations within this study, I think it's a little hard to extrapolate if we should be utilizing retaplace in the patient populations that we might see at our institution. So future studies, potentially, we could include more broad patient populations just to make it more applicable in other patients. With that, that brings me to my first assessment question. I'm curious, does your institution currently have retaplace available? And if so, is it utilized in clinical practice for the treatment of acute ischemic stroke? Okay. No, it is not yet available, and I'm not surprised by this. I know we have it available for acute MI and not for acute ischemic stroke. Personally, we don't have it available here, especially for the use of acute ischemic stroke, so I'm not surprised to see that. I think there is future data warranted to kind of figure out what our application might be and whether we should be utilizing it, but something just to keep in the back of our minds that it might be something we're leaning on after future data is available. My second assessment question for you all, based on the literature presented, would you feel comfortable administering retoplace in a patient that presents with acute ischemic stroke, assuming that the patient does meet criteria for its use? Great. I love this split. I think it's super interesting. I had to think about this a little bit as well. I think if we did have additional data, it might be interesting and I might lean on it a little bit, but I think that there is a lot of future study warranted just to ensure that it is safe and that it is effective. I think we don't necessarily know, like I alluded to earlier, the dosing. We know that there's a lot of logistical challenges that come with this two bolus approach, just if patients are transferring between hospitals or maybe they're coming into the ED, they get one bolus. How do we ensure that they get that second bolus? Given those safety factors, I don't know as though I would feel comfortable right now, given what we know about it, but I do think in the future, I might change my answer and say yes, with additional data, I would be utilizing retoplace. So I appreciate the split there. I think it's very interesting. And with that, I'm happy to take any questions that you may have. Thank you, Dr. Warfield. So, why do you think that they excluded thrombectomy candidates? Yeah, I think that's a great question. I think, in my opinion, the reason that they might have excluded patients that were getting thrombectomy, I think we need to do our data and our studies in a stepwise fashion, and I think first to utilize inpatients that aren't getting thrombectomy to ensure that the bleed risk is not as high is appropriate. And so, I think, given that it is one of the first studies that looks at the use of retoplace in acute ischemic stroke, it's appropriate to exclude those patients for now. And once we have more information available, and we assess that there isn't an increased risk of bleeding or hemorrhagic transformation, that's where I would maybe lean on utilizing it in those patients that have thrombectomy, but I think their rationale for excluding it in this study made sense to me just because we want to assess all of those factors before we start using it in patients that have also gotten a thrombectomy. I would agree. And then just, you know, obviously, we don't have this at our institution either, so just curious on the reconstitution of it and how many vials are needed per dose. Yeah, that's a great question. So it does come as a powder. I'm not certain exactly what the vial size is. I do believe it comes in the 18 milligram vials right now just because that's how we utilize it in acute MI. And so we would just be reconstituting one vial at a time for each of those bolus approaches. So one vial for the first administration, and then 30 minutes later, we'd be giving that second vial. Okay, Dr. Warfield, thank you so much for that presentation. So, that concludes our Q&A session. Now, I'd like to introduce our second presenter, Dr. Marissa Marks. Thank you for the introduction. As mentioned, my name is Marissa Marks. I am the PGY2 Critical Care Pharmacy resident at the Johns Hopkins Hospital. And the article I'm presenting today is Early Cellulococcus Abuse in Spontaneous ICH and its Association with Reduced Mortality. The incidence of hemorrhagic strokes is approximately 10 to 15% with the highest rate of mortality from spontaneous or primary intracerebral hemorrhages. Primary ICHs are caused by risk factors such as advanced age, hypertension, or diabetes, or cerebral amyloid angiopathy. Secondary causes of ICH include vasculopathy, tumor, venous thrombosis, and hemorrhagic conversion of an ischemic stroke. The pathophysiology of ICH consists of two phases. The first phase on the left occurs within the first six hours of the ICH onset and includes expansion of hematoma and metabolism of blood products. This leads to local compression of the brain tissue and increased intracranial pressure, hydrocephalus, and or herniation. The second phase, which occurs after the first six hours, is characterized by cerebral edema, inflammation, and toxicity from blood products such as hemoglobin, iron, and thrombin. The management of spontaneous ICH is currently largely supportive. This includes anticoagulation reversal, blood pressure control, glycemic control, and seizure management. In spontaneous ICH, there is an overexpression of cyclooxygenase 2, or COX-2, which causes increased inflammation and expansion of perihematobal edema that significantly contributes to ischemic brain injury. Cellococcib inhibits COX-2 specifically, which then inhibits prostaglandin synthesis and the release of free radicals and glutamate that causes the pro-inflammatory state. Therefore, there are proposed anti-inflammatory and neuroprotective properties of cellococcib in spontaneous ICH. However, there are currently no guideline recommendations to support the use of cellococcib in this patient population. However, there are previous studies to support the use of cellococcib in this patient population. The first study by Park et al. in 2009 included 34 patients with spontaneous ICH onset in the last 48 hours. Patients received 400 milligrams per day of cellococcib for at least seven days versus no cellococcib. The results showed a reduction in the volume of edema with cellococcib and no differences in adverse events. The second study by Lee et al. in 2013 included 44 patients with spontaneous ICH onset in the previous 24 hours. Patients received cellococcib 400 milligrams twice daily for 14 days versus standard of care. The results demonstrated less expansion of the parahumatoma edema and ICH with cellococcib within the first seven days. The last study by Ironside et al. study in 2021 looked at 280 patients with the onset of spontaneous ICH in the last 24 hours. Patients received daily NSAIDs less than seven days before ICH. And the results showed no difference in functional outcomes measured by the modified Rankin scale or ICH at 90 days. The hypothesis of the study is that cellococcib improves outcomes in patients with a spontaneous ICH. This was a retrospective exploratory analysis with the use of TriNetX database to identify patients with a diagnosis of spontaneous ICH. The study included three separate analyses. The first was a comparison of cellococcib within five days of spontaneous ICH versus no cellococcib. The second analysis looked at ibuprofen within five days of spontaneous ICH versus no ibuprofen. And the last analysis was a comparison of cellococcib versus ibuprofen. And for the purposes of this presentation, I'll be primarily focusing on the results of analyses one and three. The primary outcome of this study was one-year mortality. And there were various secondary outcomes, including ventilator dependence, tracheostomy, craniotomy, pulmonary embolism, deep venous thrombosis, stroke, transient ischemic attack, acute myocardial infarction, and seizures. Patients were propensity score matched based on patient demographics, comorbidities, and other confounders. Hazard ratios were used for survival analyses, odds ratios for secondary outcomes, and a Kaplan-Meier curve for the comparison of one-year mortality between cellococcib and ibuprofen. The baseline characteristics of cellococcib versus no cellococcib are presented in this table after propensity score matching of the patients. The average age of patients was 60 years old, and patients were primarily Caucasian females. The incidence of hypertension in both groups was high at approximately 70%. And it's important to note there was no difference in the percentage of patients on antithrombotic therapy between the two groups. Similar to the last slide, the baseline characteristics of cellococcib versus ibuprofen are presented in this table, again, after propensity score matching. The average age of patients was approximately 62 years old, and the patients were also primarily Caucasian females. The incidence of hypertension was slightly lower in these groups at 44%. There was no difference in any other baseline characteristics, except there was a statistically significant higher percentage of patients on ticagrelor in the cellococcib group and prasegrel in the ibuprofen group. However, the number of patients on ticagrelor and prasegrel overall were low in both groups. This graph represents the results of the primary outcome with cellococcib versus no cellococcib. There was a statistically significant decrease in one-year mortality with cellococcib at 13% versus 17% with no cellococcib. And the p-value based on these results was 0.012. This graph represents the results of the primary outcome with a comparison of cellococcib versus ibuprofen. Similarly to the comparison of cellococcib versus no cellococcib, there was a statistically significant decrease in one-year mortality with cellococcib at 14% versus 20% with ibuprofen. And the p-value based on these results was 0.0013. In this table, you can see the incidence of secondary outcomes for cellococcib versus no cellococcib. Overall, there was no statistically significant differences in any of the secondary outcomes. And similarly to the comparison of cellococcib versus ibuprofen, there also was no difference in any secondary outcomes. Overall, the author's conclusion of this study is that there was a decrease in mortality at one year with cellococcib versus no cellococcib in patients with spontaneous ICH. In addition, similar results were reported with a comparison of cellococcib versus ibuprofen. There was also no difference noted in any secondary outcomes between cellococcib and no cellococcib and cellococcib and ibuprofen. This study addressed an area of clinical practice with a current lack of primary literature. In addition, the morbidity and mortality of this disease state remains high despite current guideline recommended treatment. There are many strengths of this study to note. It was a multicenter with the largest sample size to date. This study also included both a comparison of cellococcib to standard of care, but also a comparison of cellococcib, a COX-2 selective NSAID, to ibuprofen, a non-selective NSAID. Patients were propensity score matched to decrease the risk of bias from confounders. Lastly, there is a high generalizability of this study. The patient population included matches patients that are typically at a high risk of spontaneous ICH, including patients at an advanced age with risk factors such as hypertension. However, there are also many limitations of this study that are important to consider. This was a retrospective study, which could increase the risk of bias due to the reliance on accuracy of the records. There also is a high risk of type 1 error from the required reanalysis of the information. Lastly, due to the retrospective nature of the study, they were not able to include any medication-specific information such as dose, duration, administration times of cellococcib or ibuprofen, or any assessment of functional outcomes. My conclusion of this study is that the addition of cellococcib to standard treatment for spontaneous ICH may decrease mortality without an increase in adverse events. However, randomized studies are needed to confirm these results and appropriately institute changes in clinical practice. Specifically, it would be beneficial to have more randomized controlled trials with more medication-specific information and assessment of not only mortality but also of functional outcomes. And with that, my first question is, do you use any NSAIDs as a part of the standard of care for patients with SICH at your institution? And the answer choice is, yes, cellococcib only, yes, ibuprofen only, yes, any NSAID, or no. Okay, it looks like all patients have responded no, and that is similar to the institution that I am at. We don't currently use NSAIDs as a part of the standard of care for patients with spontaneous ICH. Question number two, would you add Cellococcib to the management of patients with spontaneous ICH based on the results of this study? Yes for all patients, yes for select patients, no, or other. Okay, so interesting split between the different answer choices. Most people answered no, and I agree with that currently, just based on the amount of evidence that we have to use selecoxib in spontaneous ICH. But I think that there is potentially some benefit, considering the possible risk, but I think that more studies, specifically randomized controlled trials, would be needed to consistently institute this in practice. Thank you so much for listening to my presentation today, and I can take any questions that you have at this time. Thank you, Dr. Marks. I would agree that this study was interesting in terms of there was really no guidance on the dose or duration. And was there any mention on GI bleeds or any discussion on that? Yeah, I think that's a really great question and something that I thought about as well. Unfortunately, there was no, this was not part of the study at all, nor did they discuss it in the article. But I think that if there were hopefully to be future studies, that would be something I think would be very important to include, as this is a big risk of NSAID use in general. And since it alluded to reduced mortality, but we need more information, how would you advise, or if you were to do a research project on this, how would you like to see the study set up? Yeah, that's a really good question. Thank you. I think that I, like in this study, I would like to make it a randomized trial, but I would like to include a comparison of cellococciv versus standard of care, but I think it would also be interesting to include ibuprofen as a cohort if possible, just to compare the difference between non versus selective NSAIDs. I would also like to look at mortality, but I think it would also be very important to look at functional outcomes as well. And then kind of based on that last question that you asked, I think a really important secondary outcome would be looking at GI bleeding or just major bleeding or clinically significant bleeding in general. And then there is some kind of discrepancy between dosing and what would be appropriate to use for cellococciv. Some of these studies used 400 milligrams per day. Some of them used 400 milligrams twice daily. I think that I would probably lean towards 400 milligrams per day just because of possible risk of increased bleeding with these agents. And then they also had kind of a wide timeframe of when you would start cellococciv. Some of the studies looked at starting it early. However, you can have secondary injury from spontaneous ICH up to about 14 days after the onset. And so I think starting it and continuing it anywhere in that timeframe would be appropriate. I would probably favor, since the study started within 24 to 48 hours, I would favor starting it within that timeframe and then continuing it through that 14 days. We actually got a question from the audience that said, or that asked, did the author specify the timing that patients received the agent other than within five days? And do you agree with that timeframe? So it's funny that you brought it up. So just to recap, what timeframe would you say to start it and duration? Yeah, they did not mention any other information besides within five days. And I think that's just because of the retrospective nature of the study. I would be in favor of starting it within kind of that 24 to 48 hour after onset. But I definitely, because of the lack of literature, don't think it would be wrong to start it after that. But if I were able to control the study, then I would favor starting it in that timeframe and continuing it up to that 14 day mark where you could still see the secondary injury from spontaneous ICH. I would agree. Okay. Thank you so much, Dr. Marks. We'll go ahead and end our Q&A session. And now I'd like to introduce our final presenter, Dr. Zivia Gutman. Hi, thank you for the introduction. Good afternoon, everybody. As mentioned, my name is Zivia Gutman. I'm the PGY-2 critical care pharmacy resident at SBH Health System in the Bronx. Today I will be presenting on an article titled Neuromuscular Blocking Agents During Targeted Temperature Management for Out-of-Hospital Cardiac Arrest Patients. Today we will review background on post-arrest management for out-of-hospital cardiac arrest. We will review recent literature on neuromuscular blocking agents and targeted temperature management. We'll evaluate this recent study on neuromuscular blocking agents and targeted temperature management. And lastly, we will discuss takeaway points in the management of targeted temperature management. Some abbreviations that are used throughout this presentation, TTM, meaning targeted temperature management, ROSC, R-O-S-C, is return of spontaneous circulation, NMBA is a neuromuscular blocking agent, OHCA, out-of-hospital cardiac arrest, and RCT is a randomized control trial. Some background information. So targeted temperature management, or TTM, is the concept of therapeutic hypothermia. The idea is to slow down metabolic processes in order to reduce inflammation and cerebral edema after a cardiac arrest. Major complications of targeted temperature management include shivering and ventilator asynchrony. Generally, targeted temperature management is used in out-of-hospital cardiac arrest patients, often because we don't know the downtime and the amount of time that oxygen was being deprived from the brain. The 2023 American Heart Association focused update for cardiopulmonary resuscitation and emergency cardiovascular care recommend the following. These guidelines recommend temperature control for all adults who do not follow commands after return of spontaneous circulation, regardless of arrest location or presenting rhythm. They recommend maintaining a temperature between 32 degrees Celsius and 37.5 degrees Celsius during post-arrest temperature control for a minimum of 24 hours. Prevention of fever beyond that initial temperature control phase is recommended as well. Lastly, they recommend that patients with spontaneous hypothermia after return of spontaneous circulation who do not follow commands should not be routinely, actively, or passively re-warmed faster than a rate of 0.5 degrees Celsius per hour. There have been some studies in the literature over the last number of years, which looked at the role of neuromuscular blocking agents in targeted temperature management. Firstly, I will discuss a systematic review of meta-analysis, which showed that the use of neuromuscular blocking agents did show improved mortality over not using neuromuscular blocking agents. There was improved neurological outcomes, however, the quality of the trials in this review were weak, so further study would be needed based on this review. Lee et al. was a randomized control trial, which evaluated the effects of continuous infusion of a neuromuscular blocking agent and out-of-hospital cardiac arrest patients who underwent targeted temperature management. They found that continuous infusions of neuromuscular blocking agents did not reduce lactate levels, nor did they improve survival or neurological outcomes. This trial, however, was underpowered to detect a difference in the primary outcome. Lastly, a study by Moskowitz et al. was another randomized control trial, which evaluated whether a continuous neuromuscular blocking agent would result in a greater reduction in serum lactate levels in out-of-hospital cardiac arrest patients who underwent targeted temperature management. They found no difference between groups with a primary outcome of lactate reduction. Additionally, they found no difference in overall hospital survival, good neurological outcomes, or adverse events. So that brings us to our study here, which again is titled Neuromuscular Blocking Agents During Targeted Temperature Management for Out-of-Hospital Cardiac Arrest. The hypothesis of this study is that neuromuscular blocking agent use during targeted temperature management benefits neurological outcomes by stabilizing targeted temperature management and controlling adverse complications such as shivering. This study was a multi-center prospective observational cohort study. It included patients at least 18 years old who were transported to the hospital due to out-of-hospital cardiac arrest after achieving return of spontaneous circulation and who underwent targeted temperature management. Patients were excluded if there was missing data on the use of neuromuscular blocking agents. The primary outcome was favorable neurological outcome defined as a cerebral performance category of one to two. One being the best possible score in this scale and five being death. So one to two would be relatively favorable neurological outcomes. Secondary outcomes included in-hospital survival, the use of antibiotics for treatment during hospital stay, lactate clearance after six hours of hospital arrival, length of hospital stay, and time to achieve targeted temperature. Physicians were able to use any form of targeted temperature management and the temperature that was chosen was at the discretion of the treating physicians. For statistical analysis, one thing I'd like to point out is this concept of multiple imputation. So there were, since this was an observational study, there were missing values for a bystander CPR, witness, no flow time, low flow time, gasping, all comorbidities, lactate, pH, and hypoxic encephalopathy. This was overcome by using a multiple imputation method, which essentially placed values using an algorithm that would be plausible in order to not have gaps in the analysis. To get into the results of the study, there were 9,909 out-of-hospital cardiac arrest patients that were recorded in the system. 7,920 of these patients were not admitted to the hospital due to unsuccessful resuscitation. Of the 1,989 out-of-hospital cardiac arrest survivors that were admitted to the hospital, 548 received targeted temperature management. Of these 548, 32 were excluded due to lacking data on neuromuscular blocking agent use, leaving their total patient population for this study at 516 patients. There were 337 patients in the neuromuscular blocking agent group and 179 patients in the group who did not receive neuromuscular blocking agents. For the baseline characteristics, I'd like to highlight the following. Firstly is that the age was similar in both years, the median age in the neuromuscular blocking agent group being 63 and 67.5 in the non-neuromuscular blocking agent group with predominantly males in both groups. My next red box, the bystander CPR, was a little bit higher in the neuromuscular blocking agent group at 57.1% and 48.3% in the non-neuromuscular blocking agent group. Looking at comorbidities, we saw that hypertension was the predominant comorbidity amongst both groups, followed by diabetes mellitus, then chronic heart failure, COPD, maintenance dialysis, and lastly, stroke. Looking at the initial monitored rhythm, we saw that about 50.7% of patients had a shockable rhythm in the neuromuscular blocking agent group versus only 35.8% of patients in the group who did not receive neuromuscular blocking agents. And in terms of brain CT findings, after the return of spontaneous circulation, 32.3% of patients showed hypoxic encephalopathy on CT in the neuromuscular blocking agent group, which was lower than the 37.6% of patients who showed hypoxic encephalopathy in the non-neuromuscular blocking agent group. And then looking at the targeted temperature chosen, the majority of patients in the neuromuscular blocking agent group targeted a temperature of 34 degrees Celsius, whereas in the non-neuromuscular blocking agent group, the majority of patients were targeting a temperature of 36 degrees Celsius. And lastly, looking at the sedatives that were chosen, the majority of patients amongst both groups were receiving midazolam, followed by propofol, and then dexmedetomidine and other falling in last. For the primary outcome, favorable neurological outcomes at discharge, we saw a higher percentage in the neuromuscular blocking agent group at 38.3% compared to 16.8% in the non-neuromuscular blocking agent group, and these results were statistically significant. For in-hospital survival, we again see a higher percentage in the neuromuscular blocking agent group at 58.3% compared to 33% in the non-neuromuscular blocking agent group. These results were statistically significant as well. And then continuing in our secondary outcomes, the use of antibiotics for treatment was higher in the neuromuscular blocking agent group compared to the non-neuromuscular blocking agent group. Lactate clearance at six hours and length of hospital stay did not show a statistically significant difference between groups, and the time to achieve targeted temperature was lower in the neuromuscular blocking agent group compared to the non-neuromuscular blocking agent group, being 3.9 hours in the, excuse me, in the neuromuscular blocking agent group compared to six hours in the non-neuromuscular blocking agent group. Looking at the subgroup analysis, so this was a subgroup analysis of the primary outcome of favorable neurological outcomes amongst each group. I'd like to point out that patients who had an initial shockable rhythm in the neuromuscular blocking agent group, there were 46.2% of patients compared to 26.6% of patients in the non-neuromuscular blocking agent group. The authors of this study concluded that the use of neuromuscular blocking agents during targeted temperature management was associated with favorable neurological outcomes and survival for out-of-hospital cardiac arrest patients. Effect was seen in subgroups with the initial shockable rhythm and no poor prognostic sign on a brain CT. In terms of my critique of this study, some strains were that there was multiple imputation or missing data, and that adjustments for patient background were taken into account. Looking at the weaknesses, the groups in this study were very disproportionate. They were not equal in size. There were nearly double the amount of patients in the neuromuscular blocking agent group compared to the non-neuromuscular blocking agent group. Additionally, this was an observational study, which is an inherent weakness in any trial that we look at. There was also no information on the agents that were used as neuromuscular blocking agents, nor how they were administered, whether they were given as bolus doses or continuous infusions. And then lastly, this study took place in Japan, which makes it difficult to generalize that to our population. One other thing I'd like to point out in the secondary outcomes was that one that was statistically significant was the time to targeted temperature, which was lower in the neuromuscular blocking agent group. However, there's really no data to support that a quicker time to the targeted temperature would have more favorable outcomes for patients. It's more of just a surrogate marker. Some takeaways from this study is that there's currently not enough data to support the regular use of neuromuscular blocking agents with targeted temperature management. Guidelines recommend the use of neuromuscular blocking agents in the cases of uncontrolled shivering, but there may be some room for larger randomized controlled trials to detect a benefit in using these neuromuscular blocking agents and targeted temperature management for out-of-hospital cardiac arrest patients. This now brings me to my first polling question. Do you use neuromuscular blocking agents in targeted temperature management patients in your institution? Yes or no. So I see that the majority of our audience does not use neuromuscular blocking agents regularly in targeted temperature management. That's the same at my institution. We generally do not use these agents in patients who are undergoing targeted temperature management. And my second question is that after reviewing the current data on neuromuscular blocking agents and targeted temperature management, are you inclined to begin and or continue using them in your practice? So this one was a little bit more split, but I see the majority of participants still would say no, and I would agree with that. Based on the data we currently have with previous trials and the trial I just discussed is that there's either no benefit or not enough data to show benefit in using these agents. So I think that in order to begin using them at least in my practice, I would wanna see a little bit more data to support their use and their benefits. These are my references, and this now concludes my presentation, and I'm open to any questions. Can you discuss why you stated imbalanced sample size in the groups is a limitation? There was no pre-specified allocation since it was observational. So being that it was observational, it's obviously more difficult. You can't randomize your patients one to one. Generally speaking, I think when the groups are well balanced, it makes it easier to draw a conclusion, especially being that the first group had nearly double the number of patients compared to the second group. But that kind of goes into the weakness of the study being observational, is that they have less control over the sample size. So I see what you're saying, how being that it was observational, they couldn't control it, but I think that had the groups been more well balanced, then it would have been easier to potentially draw a conclusion here. Another question from the audience, has shivering been found to be associated with positive neurological outcome such that there will be some selection bias in this observational study? I have not come across any data to support shivering being positive or favorable in neurological outcomes. This could be something that I could potentially look into further, but it is generally associated with poor neurological outcomes. So if there is data to support that it would be more favorable, then that would open up the door to some selection bias in this study. And just curious, has your institution adopted the normal thermia recommendation or are you guys doing the TTMs? So generally for an out of hospital cardiac arrest or unknown downtime, we lean more towards TTM. We have some physicians that lean towards normal thermia, but as an institution, we still adopt the TTM policies. And then future directions for this study, which agent would you choose for the NMBA? I would probably choose Nimbax or this Saturcurium as an infusion. It tends to be well tolerated by our patients. It's easy to titrate and to assess the response to the agent. We use it for other times when we use paralysis in our institution and it's a very user-friendly agent, I would say in this area. Another question from the audience, what is the standard protocol for shivering? For shivering, the guidelines would recommend using a neuromuscular blocking agent to paralyze the patient in order to prevent further shivering. Okay, thank you Dr. Gutman. So that will conclude our Q&A session. So 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 Eastern Standard Time for the Next Journal Club Spotlight in Pharmacy and that concludes our presentation today. you

Webcast

Pharmacology

Neuroscience

Resuscitation

Targeted Temperature Management

Anticoagulation

Intracerebral Hemorrhage

2024

Professional

Select

critical care pharmacy

RAISE trial

retoplase

alteplase

acute ischemic stroke

celecoxib

neuromuscular blocking agents