Hello and welcome to today's webcast for neuropharmacology. My name is Krista Ohananobleza and I'm the medical director at Baptist Memorial Hospital and an associate professor of neurology in University of Tennessee Health Sciences in Memphis, Tennessee. I will be moderating today's webcast. A recording of this webcast will be available within five to seven business days. Log in to mysccm.org and navigate to the My Learning tab and click on the neuropharmacology course. Click on the access button to access the recording. Thanks for joining us. So a few housekeeping items before we get started. There will be a Q&A at the end of the presentation. To submit questions throughout the presentation, type in your questions into the question box located on your control panel. 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. Nicole C. Davis is a clinical pharmacist at Mount Sinai Hospital in New York, New York. Andrew Webb is a clinical pharmacy specialist at Massachusetts General Hospital, Neurology, Neurocritical Care, Department of Pharmacy in Boston, Massachusetts. Salia Farouk is a pharmacist at Johns Hopkins Hospital in Baltimore, Maryland. And now I'll turn things over to our first presenter. Hi, everyone, and welcome to my talk on anticoagulation and antipoietic reversal. My name is Nicole Davis. I'm a neuro ICU pharmacist at the Mount Sinai Hospital. So we will talk about the strategies on how to reverse anticoagulants, as well as identify specific ones, as well as their correct reversal strategy. And then we'll address antipoietic reversal at the end. These are the common acronyms I'll be using throughout my presentation today. When it comes to preparing for your boards, these are the two guidelines that you absolutely do have to know. I have some other recommended reading throughout the presentation, but the Neurocritical Care Society Anticoagulation Reversal Guidelines and the 2022 AHA ICH Guidelines that will also address anticoagulation reversal, these are need-to-know topics. This is the algorithm that the AHA uses within their ICH guidelines, so this is what we will spend the most time discussing today, but I will address all anticoagulants. So when it comes to reversal, there are some things that you should consider. Most importantly, when was the last dose taken and if enough time has passed? So for example, if I'd say three to four, three to five half-lives have passed, there's probably not much drug left to reverse, and therefore, administering a reversal agent may be riskier than the benefit that it could provide. Other things to consider, does the patient have an AKI, as some anticoagulants do require renal function or adequate renal function to be cleared appropriately, so if they have AKI, the half-lives could be prolonged, such as with DOACs and low molecular weight heparins. Some agents, such as PCCs and indexin, are prothrombotic, so the risk always has to be balanced with the benefit. Additionally, some agents can be re-dosed, so four-factor PCC, protamine, and iduricizumab may all be re-dosed if the clinical exam indicates that bleeding is worsening or there is still anticoagulant present. Additionally, for all the oral anticoagulants, if they were ingested within the last two hours, you may administer activated charcoal, but just be cautious because it can induce vomiting in patients who don't have a secure airway. So this is a slide that I do not expect you to remember, but you can refer to it, especially focusing on those that have renal elimination, as these are the agents that can be prolonged in AKI, so you may need to consider administering a reversal outside of its three to five half-lives. Additionally, the half-lives are also here for you, just to give you a guide on about how long it's appropriate to administer a reversal. So starting with our first agent, we're going to talk about warfarin. So warfarin inhibits factors 2, 7, 9, and 10, and this does play a role in the type of agent that we would choose to reverse with. So when it comes to reversing warfarin, you should take a two-pronged approach. The first agent that you're going to administer is four-factor PCC. So four-factor PCC is a highly concentrated clotting factor complex concentrate. So it contains factors 2, 7, 9, and 10, as well as protein CNS, and it also contains a little bit of heparin. Whenever you administer four-factor PCC, you will see significant INR decreases very quickly, and it has an effect of around six to eight hours, so this kind of plays a role whenever you're considering administering an additional dose, because it can wear off. As far as the dose, it is going to be institution-specific. You can utilize either fixed dose or a weight-based package insert dosing, and it can be administered via IV push. If you choose to re-dose, the re-dose is typically around 500 units. The second-pronged approach that you need to initiate is give vitamin K. So vitamin K will stimulate the liver to synthesize factors 2, 7, 9, and 10. So vitamin K is kind of thought to be the classic reversal agent, and the four-factor PCC is going to be administered to stabilize the hemorrhage and initiate that thrombin burst. So vitamin K, the dose is 10 milligrams, and you administer over 10 to 30 minutes, because it can be associated with anaphylaxis. But it does have a slow onset of action, so that is why it has to be given with four-factor PCC, because its peak effect is around 48 hours. So whenever you're administering both, give your PCC first, followed by your vitamin K. As I mentioned before, PCC is likely going to be dictated by the institution that you're working at, but you can use either a fixed dose regimen of 1,000 to 2,000 units, or you can utilize the patient's pretreatment INR, as well as their weight, and use the package insert of 25 units per kilo up to 50 units per kilo, depending on the INR. So while this is helpful, because it is package insert dosing, it does require you to know the patient's weight and their INR, and it is possible that you could over-treat the patient, as well as increase the cost, whereas with fixed dosing, it is faster, because you need to know less information, and it has been associated with cost savings. The retrospective data available has indicated that it is just as effective, though the ideal dose is still unknown. There's also some caveats in patients with obesity, and those with extremely high INRs, as they were not studied as well. Additionally, because the four-factor PCC does contain heparin, avoid it in patients who have a history of HIT, and utilize either three-factor PCC, activated PCC, or FFP. So this brings me to my first slide of recommended reading. These are all of the landmark warfarin reversal trials, so if you do have time, I do recommend taking a look at these and giving them a read, as these are the main trials that have guided warfarin reversal. Changing gears from warfarin, we'll discuss the factor Xa inhibitors, apixaban, rivaroxaban, and adoxaban. So when it comes to factor Xa inhibitor reversal, this is where it does get a little bit controversial, as there are two options, and at this point in time, either option would be appropriate. The AHA recommendations do give a slightly higher grading to indexonet, but that's just because the RCT with indexonet versus usual care had not been published at that point in time. Just be aware, with where the evidence stands now, four-factor PCC or indexonet is appropriate. So as we discussed with four-factor PCC, it's going to create that thrombin burst, and the dosing for it is similar to warfarin, either doing 25 to 50 units per kilo, or a fixed dose regimen, and you can re-dose with the same thought process as you would for warfarin. With indexonet, indexonet is a specific reversal agent that reversibly binds and sequesters Xa inhibitors and inhibits the activity of tissue factor pathway inhibitor. So via two mechanisms, it binds the anticoagulant, and then it also will increase thrombin generation. Its half-life is shorter than four-factor PCC, and it does require an infusion to function. So you give a bolus followed by an infusion, and it's going to be dependent on the amount that was of the anticoagulant that was ingested, as well as when it was last ingested. So each hospital will likely determine if you are able to use indexonet or PCC. Some places have added indexonet to formulary, others have not. The reason that it has not been universally added is it is more expensive than PCC, and the evidence supporting it is a little bit ambiguous. So as I mentioned before, the AHA has given a higher grading to indexonet prior to a NEXA-I publication. So NEXA-I was published in May of 2024, and it did show improved hemostatic efficacy with indexonet, but it did have significantly more thrombotic events in the indexonet arm as compared to usual care, and it was primarily driven by increased ischemic stroke. And then in the usual care arm, only 85.5% of patients received PCC, so even though we had hoped that this would be a PCC versus indexonet, in the usual care arm, some patients did not receive PCC. So with this caveat being said, there was no difference in mortality or 30-day outcomes. So at this point in time, you can utilize either agent to reverse your factor X-As. So this brings us to our first case of a patient receiving apixaban with confirmed ICH. So the correct answer would be to initiate nicardepine or some type of blood pressure agent as his blood pressure is elevated, and then you can order an immediate dose of four-factor PCC at a dose of 2,000 units. So there could be multiple right answers for this case, but of the answer choices provided to you, A is the most correct answer. You would not administer vitamin K, and you would not administer protamine, and you certainly would not initiate norepinephrine. The next DOAC that I'll discuss is dabigatran. So dabigatran is a direct thrombin inhibitor. The reversal agent used to reverse dabigatran is idarocizumab. Idarocizumab irreversibly binds to dabigatran and its metabolites to neutralize its anticoagulant effect within minutes. And unlike indexonet, idarocizumab is an irreversible reversal agent, meaning that once it binds to dabigatran, it does not come unbound, whereas indexonet will become unbound, and the patient in theory could be re-anticoagulated. Idarocizumab also is not thought to have any type of prothrombotic aspect to it, like indexonet and PCCs do. You can see its effect within minutes, and it has a lasting effect of around 24 hours. It's dosed as a 5-gram single dose, and you can administer that via IV push, and you may re-dose if necessary. Dabigatran also can be removed by hemodialysis, so that is another option to reverse it. So this is a case that is a little bit more gray. So this is a patient who has an ICH on dabigatran, and you have to determine if it's appropriate to give reversal. So the appropriate reversal agent is idarocizumab, but she has not taken a dose in 5 days, and she appears to have normal renal function, labs checked. So this would be a case where, based on its half-life, 3 to 5 half-lives have already elapsed, so it actually would be appropriate to not give reversal, but because idarocizumab is not pro-thrombotic, if you did choose to administer a dose, I don't think that's incorrect either, but I think the best answer choice here would be no reversal as indicated. And then here are the recommended readings, so the idarocizumab trial that got idarocizumab FDA approved, as well as the most recent annexa I trial that was in randomized to usual care versus indexinib. And then finally, the FIX-ICH, which was the largest PCC trial that we have available to us today. So great readings for DOAC reversal. So that wraps up the oral anticoagulant reversal, so now we'll talk about the heparins. So heparin and oxaparin works by potentiating antithrombin, and antithrombin then will go to inhibit factor X as well as thrombin in different ratios depending on which agent that we're discussing. So when it comes to heparin reversal, we do have a specific reversal agent, protamine. So protamine will bind to heparin via covalent bonds to form an inactive complex. The dosing is specific, which I will discuss in just a moment, but with protamine, it is the Goldilocks reversal agent, just because it does have some adverse effects if you overdose it, one of those being actual increase in anticoagulation, which I'll discuss in a moment. But it also is associated with hypotension, bradycardia, bronchoconstriction, as well as possibly anaphylaxis or vasoplasia, as seen in cardiac surgery patients. So the maximum dose that you're going to give is going to be 50 milligrams, and if for some reason the patient cannot receive protamine, you can consider activated factor VII. And then finally, whenever you're reversing heparin, you're only going to reverse patients who have received an IV bolus or a continuous infusion. You should not reverse DVT, prophylaxis-dosed heparin, unless the PTT is prolonged. So as mentioned before, it being a bit of the Goldilocks reversal agent, if you underdose your protamine, it's possible that there'll still be heparin unbound and it will continue to increase bleeding complications, but protamine in and of itself is actually a very weak anticoagulant. So if you just overdose it and overshoot the amount of heparin, you can actually theoretically increase your patient's risk of bleeding. So this does mean you need to be thoughtful in how much protamine that you're going to administer. In general, one milligram of protamine reverses around 100 units of heparin. So if you have a heparin infusion, you're only going to consider giving as much protamine as there has been heparin in the preceding two and a half hours as it has a short half-life. And if you consider any longer, it could, in theory, overdose the patient. So I did provide an example for you of a patient who was receiving 1,000 units per hour of heparin. So you would take the heparin given in the last two and a half hours, so 2,500 units, and then one milligram of protamine reverses 100 units of heparin. So if you divide that by 100, you'll get that you need to give 25 milligrams to appropriately reverse this heparin infusion. You can reduce the protamine at a dose of 0.5 milligrams per 100 if the APTT still is prolonged. So this brings us to our third case. So this is a patient on a heparin infusion and then developed an ICH. So just like the example on the previous slide, you'll calculate how much heparin she received in the last two and a half hours. So around 2,600 units. Divide that by 100, and you'll get that you need to give 26.8 milligrams of protamine. I always round it to the nearest whole number, so B would be your most appropriate answer. For enoxaparin, we will actually still use protamine to reverse it. Protamine unfortunately is not as attracted to enoxaparin as it is to heparin, so it is a little bit less effective at reversing enoxaparin than it is heparin. So if your patient has taken a therapeutic enoxaparin dose in the last eight hours, you'll give one milligram of protamine per milligram of enoxaparin up to a maximum dose of 50 milligrams. If they received it in the last eight to 12 hours, it'll be a half milligram of protamine per milligram of enoxaparin. And then if they took their enoxaparin more than 12 hours ago, it's not recommended to give any protamine at that point, unless they have some kind of AKI that's prolonging the half-life of enoxaparin. If for some reason your patient cannot get protamine, activated factor VII or indexonate are the alternatives. So then the last heparinoid is fondoparanox. So unfortunately because fondoparanox is a very short pentosaccharide, protamine is ineffective as protamine is just not attracted to fondoparanox, so it's unable to bind to it. So the only option that we have for fondoparanox is some type of PCC product. The neurocritical care guidelines recommend utilizing activated PCC, overactivated factor VII. As far as just four-factor PCC, not a lot of data to support it, so I think whatever you have available you can utilize. And I did include the dosing for you on the slide. The last anticoagulant we'll discuss today are the direct thrombin inhibitors, bivalirutin and argatraban. So with these agents, you typically don't have to reverse them because they do have a very short half-life, so by the time that you've identified that an ICH or other massive bleed is occurring, you've likely already turned your infusion off and it's already working its way out of the system. But if you do deem that the patient does need some type of reversal, your only options are going to be PCC or activated PCC at the high dose of 50 units per kilo, just because PCC products are not extremely effective for reversal, but it is kind of the best option that we have. Iodarizumab is not an appropriate reversal agent for these agents, as Iodarizumab was designed only for dabigatran, so therefore it is unable to bind to bivalirutin or argatraban. And you would monitor APTTs to assess for clearance. So wrapping up this talk, talking about antiplatelets, so when it comes to antiplatelet reversal, you should not be using platelets. This was mentioned in the neurocritical care guidelines as well as the AHA ICH guidelines. This is based on the PATCH trial. The PATCH trial indicated that it's possible that platelets given for antiplatelet reversal could be associated with harm and increased mortality, though there's the caveat that patients who are receiving a neurosurgical intervention are excluded and then therefore may get platelets. So depending on which agent you're trying to reverse, desmopressin is likely appropriate for all options of clopidogrel, prastogrel, ticagrelor, and aspirin, so keeping in mind that clopidogrel, prastogrel, and aspirin have a longer duration of effect because they irreversibly bind to platelets. So it is worth giving desmopressin outside of their half-life window. And then with kangalore, kangalore is an IV P2Y12 option, extremely short half-life, it's only minutes, so you really do not need to give any type of reversal for kangalore. So if you're going to give desmopressin, the dose is 0.3 to 0.4 mics per kilo, and it works by increasing blood levels of factor VIII and von Willebrand factor, as well as a few other mechanisms that are useful when treating diabetes insipidus. It does work within 30 minutes and has a duration of effect of 6 to 14 hours, and its major adverse effect is hyponatremia, though it's unlikely to occur with a single dose. That risk of hyponatremia likely only increases when you re-dose it several times. And when it comes to antiplatelet reversal, the re-dosing is not well established at all. So that does conclude my talk on antiplatelet and anticoagulation reversal. I hope everyone found something useful from this discussion. Thank you so much. All right. So we're going to transition now into something different, and that is the pharmacotherapy of status epilepticus. All right. So to start off our discussion, I think it's important to frame what we're going to talk about over the next 15 minutes or so with a patient case. Those of you who work in emergency medicine or in critical care have likely seen a case like this, and hopefully the discussion about the rationale for why we use the medications that we do will make sense in the context of this case. So suppose you have a 32-year-old woman with no significant past medical history who's brought to the ED by EMS after her partner found her unresponsive and convulsing in the bathroom. It's uncertain how long she was there, but seizure-like activity occurred for at least 10 minutes prior to EMS arriving. In the ED, her vital signs are an SpO2 of 98 percent, she's on two liters of nasal cannula with a respiratory rate of 14 breaths per minute. Her blood pressure is 108 over 64, and her heart rate is 113, and the finger-sick glucose done in triage is 98 milligrams per deciliter. And so with this, we're going to go through the rationale for the work, kind of the step-by-step approach to managing a patient in status epilepticus, as well as the landmark trials which inform those treatment decisions, which will be important for the neurointensivist to know. So first things first, I think it's important to mention what guidelines we base our medication decision-making on. Currently, there are two guidelines which exist for the treatment of status epilepticus, one supported by the Neurocritical Care Society, published in 2012, and one supported by the American Epilepsy Society, published in 2016. There are ongoing efforts to update these guidelines, but these are the most recent published guidelines which we currently base our treatment recommendations on. So when I think about treating a patient with status epilepticus, I really try to think about this as sort of a latter approach of escalating management with the ultimate goal of stopping seizure activity as fast as possible. So I won't go too much into detail with the pathophysiology or the definitions of status epilepticus, but you're likely familiar with the escalating stages of status epilepticus, which progressively are associated with the worst prognosis. And so when you have a patient who presents to the emergency department or who develops status epilepticus in the intensive care unit, really should think about managing that patient in a stepwise algorithmic fashion. The first step really being ensuring you're stabilizing your ABCs, identifying and documenting the time of seizure onset, and getting a finger stick glucose. And then from there, if the seizure does not resolve spontaneously, this is where you start to institute the pharmacotherapy which we're going to discuss over the next 15 minutes. The first line therapy, which is defined as emergent therapy in the NCS guidelines is always going to be a parenteral benzodiazepine with repeated doses of seizures continue. If seizures continue despite those first line appropriately dose parenteral benzodiazepines, that patient would be considered to be an established status epilepticus. You would progress to urgent therapy with anti-seizure medication, and ideally apply continuous EPG to help guide your therapy. If patients progress beyond that urgent therapy, that administration of intravenous anti-seizure medications, that will then be defined as refractory status epilepticus, where the evidence starts to become quite a bit more thin, and practice decisions need to be made in a patient by patient basis. If patients progress through that refractory treatment, which generally refers to the initiation of anesthesia, that patient would be considered to be super refractory. That's where there are more nuanced therapies which are considered for these patients. And so considering this algorithm, we're going to go through each of these in a little bit more detail, to introduce you to the data which support the medications that we choose, and importantly introduce you to the dosing and considerations for choosing those agents. So first, I want to introduce that benzodiazepines are first line emergent therapy for patients who present with status epilepticus. So as a reminder, status epilepticus is defined as seizure activity that lasts for five minutes or longer, or two independent seizure episodes without recovery of consciousness in between. And in a patient presenting in that state, such as our patient that I presented earlier, a high appropriately dosed parenteral benzodiazepine is going to be first line. That therapy was established in the VA cooperative trial, a randomized control trial published in the late 90s, where benzodiazepines, specifically lorazepam, was shown to be the best therapy overall, compared to phenobarbital, diazepam in combination with phenytoin, or phenytoin alone. These four arms were administered in a double dummy fashion in this randomized control trial. And as you can see here in this figure here on the right, lorazepam had numerically the highest rate of seizure cessation compared to other therapies, and was also found to be the most convenient and best tolerated overall. So really from this trial, lorazepam and in general benzodiazepines were established as the most effective and convenient therapy as emergent treatment of status epilepticus. And here also the dose is very important. The dose of lorazepam used in the VA cooperative trial was 0.1 milligrams per kilogram, with a maximum, generally speaking in clinical practice now, of four milligrams, which is carried forward into the clinical practice guidelines we use today. Now one thing I also want to point out is that while the VA cooperative trial treated patients in the emergency department, really the thing that we've understood now is that the earlier you can get a benzodiazepine into a patient in status epilepticus, the better. And so the PHTSE trial was a pre-hospital randomized control trial, which essentially randomized patients who EMS responded to in status epilepticus to either lorazepam, diazepam, or placebo. And essentially as you can see here on this figure here on the right, this is a survival curve for patients who are persistently in status epilepticus after the administration of their randomized treatment. What they found is that versus placebo, lorazepam had a significantly higher likelihood of terminating status epilepticus when administered in the field. Now one thing I do want to point out is you may see here is that diazepam is also listed here on this chart. And while diazepam was generally effective in this arm, because diazepam's pharmacokinetics are such that it's so lipophilic that while it enters the CNS very quickly, it also leaves the CNS very quickly. Essentially, the duration of anti-seizure activity is too short for diazepam to be a preferred first-line agent in status epilepticus. And so because of this, this is another support for lorazepam specifically being the first-line agent. One thing I also want to point out is that out-of-hospital complication rates for lorazepam were lower numerically compared to placebo. And so here is just one example of how adequately treating a seizure with a high-dose benzodiazepine is better than allowing that seizure to continue. And so concern for respiratory compromise should not prevent you from using an appropriately-dosed benzodiazepine. And again, just pointing out once more that the status dose of lorazepam is 0.1 mg per kg, up to 4 mg per dose. Now, and again, pointing this out, as I previously said, because diazepam's duration of seizure activity is shorter than lorazepam, if that's the only benzodiazepine you have access to, certainly it is a viable option. But lorazepam is the generally preferred option overall. Now, the next question you might ask is, say, if you are in the pre-hospital setting or if you're in a context where you may not have IV access, can you shave off time by giving a benzodiazepine intramuscularly? And so the RAMPART trial looked at that specifically by randomizing patients in status epilepticus in the pre-hospital setting to either intramuscular midazolam or intravenous lorazepam. And while it was designed as a non-inferiority trial to try to assess whether or not midazolam could be just as good as lorazepam, what they actually ended up finding was that midazolam was actually superior to lorazepam in the overall population. And likely the reason for that is because midazolam could be administered faster because EMS does not have to establish IV access. Basically, the lesson here is that whatever benzo you have that you can get into the patient the fastest, that's dosed appropriately and given in an appropriate manner, is going to be best for patients. And so in this figure here on the left, basically, the time to seizure termination from when the drug was actually given was similar between the two agents, but essentially patients who did not already have IV access, being able to give an IM agent was going to be better in that context. So really expedient access matters more than the choice of agent. One thing I do want to point out, however, is that IM lorazepam has erratic and slow absorption, and so lorazepam should not be used as an intramuscular agent if that's what you're going to go for. And to point out here, the dose of intramuscular midazolam for status epilepticus is different. It's going to depend partly on weight, but for most adult patients, the intramuscular dose is going to be 10 milligrams per dose. So concluding with our emergent therapy, basically appropriately dosed parenteral benzodiazepines are going to be first-line emergent seizure management for all patients in status epilepticus. I've presented here a brief table for your reference that goes over the IV onset time for each of the benzodiazepines, the duration of peak seizure activity, as well as the half-life of the agent in the equipotent dose. From a pharmacokinetics perspective as well, we generally think of lorazepam as having a longer seizure activity than the other benzos, but certainly you want to use whatever you have available as soon as possible. And so for our first question, we have that 32-year-old woman who presents to the emergency department for presumed status epilepticus. The evaluating physician is concerned for early generalized convulsive status, and which of the following is the most appropriate emergent therapy? And so here, of all of the doses, midazolam IM10 milligrams is the appropriately dosed agent for this particular patient. While diazepam or lorazepam could be available options, it's important to be aware of the doses that are appropriate for these patients. So kind of coming back to our algorithm here, if we do have a patient who presents with that early status epilepticus, it's important to give emergent first-line benzodiazepines at appropriate doses. One thing I do want to point out is with those doses, if a patient does not respond to the first dose of that appropriate dose, so 0.1 milligrams per kilogram for lorazepam, generally a maximum of 4 milligrams per dose, for midazolam at 10 milligrams, you should repeat a dose if a patient is persistently seizing after about five minutes. However, not all patients are going to respond to that first-line benzodiazepine. And so if a patient continues to seize beyond that appropriately dosed first-line benzodiazepine, the next thing you're going to get into is the urgent therapy for status epilepticus. And so the principles of therapy for urgent therapy is going to be giving a large, appropriately dosed, once again, intravenous, intermittent anti-seizure medication. And so the principles of therapy for urgent therapy medication. Generally speaking, the three IV anti-seizure medications we consider as appropriate urgent therapy are going to be levotiracetam, phenytoin, or phosphenytoin, and valproate. And so the best evidence currently available in deciding between these three agents comes from the ESET trial, which was published just a few years ago. And the ESET trial randomized patients with established status epilepticus to levotiracetam at a dose of 60 milligrams per kilogram, phosphenytoin at a dose of 20 milligrams per kilogram, and valproate at a dose of 40 milligrams per kilogram, each of them having maximum doses for patients weighing 75 kilos that are listed here on the slide. So levotiracetam at a max of 4,500, phospheny at a max of 1,500, and valproate at a max of 3,000 milligrams. Ultimately, what they wanted to see is how, what the proportion of patients who actually had seizure termination, so improving responsiveness, and actual cessation of seizure activity at 60 minutes. And essentially what they found is that the probability of any of these agents being better than the other was about 50 percent, and basically patient seizures stopped about half of the time for all of the agents. And so essentially the conclusion here is that all three of these urgent therapies appear to be equally effective, and so the choice should be individualized to your patient. So I kind of have a busy slide here, which goes over some of the mechanisms of actions, dosing, maintenance dosing, whether therapeutic drug monitoring is required for any of these agents, really just to provide you with some of the reasons why we may choose one agent over the other. And I'm going to kind of go through a few key details here for why you may choose one over the other. So levotiracetam, all the way on the left-hand side, an SV2A receptor modulator, essentially one of the advantages of this agent is it is generally very well tolerated with very few side effects and very few drug interactions. And so oftentimes levotiracetam is chosen because it tends to be well tolerated in most patients and doesn't have very many drug interactions. You may want to avoid levotiracetam in a patient who you know has a significant psychiatric history because this could potentially exacerbate that underlying illness. Fosfenitoin, while historically has been used for a long time and is very effective in status epilepticus, does come with a number of notable adverse side effects, including hemodynamic instability, and a post hoc analysis of the ESET trial did suggest that it may independently increase the risk of requiring intubation. And additionally, fosfenitoin comes with a number of drug interactions. And so because fosfenitoin is a CYP3A4 inducer, it can accelerate the clearance of many medications which go through that system, which is something to be very important to be aware of if you're going to continue a patient on fosfenitoin therapy. Valproate simulate does come with some drug interactions and additionally, a number of side effects. One thing that's oftentimes important to keep in mind with valproate is the fact that it can be profoundly teratogenic. So oftentimes you may want to avoid valproate in the patient who is childbearing age, is currently pregnant, or is planning to become pregnant. Valproate doesn't have quite as many drug interactions as fosfenitoin does. One of the interactions I do want to point out specifically for intensivists is the interaction between valproate and carbapenems, however. Interestingly, carbapenems actually accelerate the clearance of valproate. And so if you have a patient who's on valproate with stable levels, the initiation of a carbapenem will actually significantly decrease valproate concentrations in a manner that's very challenging to overcome. And so essentially a patient who's either already on a carbapenem, you really should not initiate valproate as well as vice versa. And so coming back to our patient who is in the ED who got two doses of intramuscular midazolam and did not have resolution of her seizure, what would be the next most appropriate therapy? Would it be valproate 20 milligrams per kilogram at a dose of 1300 milligrams, fosfenitoin at a dose of 10 milligrams per kilogram, which is 650 milligrams? Should you just immediately intubate and initiate midazolam, or should you load levotiracetam at a dose of 60 milligrams per kilogram, which equates to 3900 milligrams? And so in this context, again, the dose is very important. And so levotiracetam here at a dose of 60 milligrams per kilogram is going to be most appropriate here. Valproate and fosfenitoin could be reasonable options, but the dose is important to keep in mind. And additionally, she is a 32-year-old woman, so it's important to keep in mind whether or not she's currently pregnant or planning to come pregnant, or that's kind of in her current history, and maybe a consideration for both valproate and fosfenitoin. So if a patient persists in seizure activity or does not seem to be responding to that urgent therapy, the next line after kind of trying these three equally effective agents is going to be entering what we call refractory treatment. Now, generally speaking, patients in refractory status epilepticus, you know, here's where data is very slim and there's limited evidence to say what is best in terms of what's next. But generally speaking, refractory treatment is going to be considered anesthesia, where seizure activity persists despite those anti-seizure medications, and so essentially intubating the patient and giving anesthesia is going to be the next line. Now, there's not a gold standard in terms of what's the best agent, but propofol, midazolam, and pentobarbital are the three agents which are typically considered, and I've listed the doses and some considerations here. Propofol is oftentimes used because it's fast acting and can be easily titrated, but recognize that doses oftentimes need to be very high to achieve seizure suppression, reverse suppression, and closely monitoring for propofol-related infusion syndrome is very important. Midazolam is also very commonly used, is also very quickly able to be started in bolus, but do also recognize that the doses may need to be very high with midazolam as well. Pentobarbital is less commonly used these days, is very effective, but it's important to recognize the high risk of toxicity, both from a hemodynamic perspective as well as the many different side effects really in all organ systems that come with pentobarb, and I've listed some of those on the slide. Now, generally speaking, even if you are initiating anesthesia for refractory treatment, additional anesthesia medications may be considered to be layered on to ensure that seizures are stopped. I've listed three additional intravenous options for patients which may be reasonable to consider, recognizing that there's limited evidence guiding the initiation of any of these three agents, and you generally need to make these decisions on a patient-by-patient basis. Now, if a patient really progresses beyond refractory treatment, so you've intubated the patient, you've initiated anesthesia to try to either achieve seizure suppression or burst suppression, super refractory treatment is really where things start to get quite a bit more gray. We won't spend too much time there, but before we get there, we'll just kind of wrap up with our last case question. So again, we have our 32-year-old woman who's now been in the neuro ICU for nine days for refractory status epilepticus. After the two doses of midazolam she got and the load of levotiracetam, she ultimately proceeded to be intubated and was initiated on propofol and is currently on 100 micrograms per kilogram per minute of propofol, as well as midazolam IV 40 milligrams an hour. And for her anti-seizure medication package, she is on levotiracetam 2,000 milligrams twice a day, leucosomide 200 milligrams twice a day, valproate 750 milligrams every eight hours, and colobizam 20 milligrams twice a day. At this point, her continuous EEG does show 80 to 90 percent burst suppression, but on rounds, you notice that she's newly hypotensive and bradycardic. A 12-lead shows a brugada-like pattern. And after initiating supportive measures, the next question is what the most appropriate management step is. And here is an important step to recognize the signs of propofol-related infusion syndrome. In patients who are on high-dose propofol for status epilepticus, they are at a higher risk of developing the side effect. And here are some of the important labs to check to monitor for that, as well as, of course, stopping the propofol if that's the highest likelihood of suspicion. So again, as I said, the therapies for super refractory status epilepticus are beyond the scope of this presentation, but may include prolonged burst suppression, immunomodulatory therapy, ketogenic diets, or even more extreme therapies in there that really should be initiated in consultation with expertise. So in conclusion, status epilepticus is a neurologic emergency that can cause long-lasting neurologic injury if not promptly recognized and treated. Treating status should follow evidence-based algorithms with aggressive IV anesthesia medications. And successful management of status epilepticus really starts with appropriate and high-quality pre-hospital care and then succeeds with excellent emergency and neurocritical care from there. Thank you so much. Today, I'm going to talk about pharmacologic management of ICU delirium and then non-pharmacologic interventions that may be helpful. And then, obviously, at the end, we'll talk about the literature and what might be the newest recommendation. As you probably know, delirium is defined as a disturbance in attention and deficit in at least one other cognitive domain. What is unique about delirium is that it happens acutely and it can fluctuate over time. Delirium can manifest as hyperactive, hypoactive, or mixed. What is important to consider when we think about delirium is that delirium should not be really explained by any other causes such as dementia or coma or, importantly, other organic cause or causes. So if someone is overdosed or has other reasons for this acute manifestation, we can't really call it delirium. To help with the diagnosis, there are different scoring systems. So, for example, there is the, as you can see, ISD-DSC, which is a scoring system. If the score is over 4, that is confirming the diagnosis of delirium. And then there's a kind of older version, which is the CAM-ICU, which a lot of institutions are still using, and that could also be utilized to diagnose delirium. What is unique about delirium, in my opinion, is that the path of this is very fascinating and it's very complex to the point that that may explain why we don't have a magical treatment for it, right? A lot of people propose that this could be an anatomical abnormality. Some have said that this is a vascular dysfunction, or it could be the direct neurotoxic effects of inflammatory cytokines such as IL-6. And then there might be some component of neurotransmitter imbalance. Specifically, there are conversations and proposals about higher than normal dopamine levels or lower than normal acetylcholine levels. This is, I think, a visual kind of confirmation of what we talked about and how this is multifactorial and there is different pathways involved. What about risk factors? Some of these risk factors are non-modifiable, so age definitely is something that comes into play. Also, pre-existing comorbidities such as dementia or depression, these are the things that might not be reversible or fixable when patients are in the ICU. But as you can see, there's a lot of other factors that we can definitely help with. There are infections that could cause or participate delirium, electrolyte disturbances, drug withdrawal, and also drug overuse such as sedation, specifically benzodiazepines and opioids, and we'll talk a little bit more about that. This is one of the studies that I like to show on rounds also, and this was published in 2006, talking about how benzodiazepines are considered to be an independent risk factor for transitioning patients into delirium. As you can see, this graph here shows that there might be a dose-response relationship, meaning that the higher the dose, the higher the probability of transitioning our patients to ICU delirium, so that should be factored in when we talk about ICU delirium. The incidence is unfortunately very high. 60 to 80 percent of our patients in the ICU settings suffer from ICU delirium, and mortality can be as high as three times of the normal ICU patients. Despite all the bad news that I just shared, the nice thing about ICU delirium is that it is a reversible process, meaning if you can recognize and prevent that from happening, you can definitely help our patients. We'll talk about prevention first in pharmacologic and non-pharmacologic. I'm not going to spend a lot of time talking about prevention, but it's important to notice that there aren't a whole lot of pharmacologic agents that can help with delirium, but then there's a lot of non-pharmacologic interventions we can do that can help with delirium, specifically making sure that we're reorienting our patients, we're doing early mobility, we're removing devices that are not necessary, using eyeglasses and hearing aids, correcting electrolyte abnormalities or dehydration, and obviously minimizing noise or unnecessary stimulation, which we talked about in our patients, if they need to be woken up every hour, every two hours for their neuroexam, it can be minimized, but it's possible. Another piece of information I want to just share here, which I think is very important, is that, you know, if you all looked at someone's medication list, we may be able to recognize anticholinergics very easily, and we know that anticholinergics and benzodiazepines are repeatedly reported to be causing delirium, especially in older patients, but sometimes these anticholinergic medications may not be as obvious, and there is a hidden anticholinergic activity in some of the medications that we may not really recognize initially. A good example is some of our antipsychotics, such as CCAs or metiproline, might have that activity. Even some of the SSRIs can have that. Another agent that I think it's worth discussing here because we use it for shivering is metaridine that can have an anti-cholinergic activity, and the benzodiazepines that we already talked about. Obviously, it's important to note that if you are receiving benzodiazepines, you have to make sure that there is a paper in place if they've been on it for a long time, and if there is a specific reason that the patient really needs to be on it, just like what we talked about in the prior lecture, then the patient has to stay on it. Moving on to the treatment interventions, as of now, despite the high morbidity and mortality, there isn't an FDA-approved pharmacologic treatment for delirium, but as you know in the ICU setting, this is nothing new. We have a lot of drugs we're using that are not FDA-approved, so the next question is, what about the guideline recommendation, right? So ironically, even the guidelines moving from 2002 from, you know, the pain agitation delirium guidelines, now all the way to 2018, Devlin's POTUS guidelines, they're not really recommending any of the antipsychotics to be used. The only agent that we think might be helpful in people that are incubated and they cannot be excavated because of agitation is dexamethamidine. We'll talk a little bit more about antipsychotics and where they may come into play, but as a general rule, it looks like less is more, and non-pharmacologic interventions may be more helpful, and if you have a patient with agitation and you can't excavate them because of agitation, dexamethamidine might be your agent of choice. So starting with the cases, and I understand that we're running out of time, but this is a patient who comes in technically with high alcohol levels, and this patient is delirious. This patient is ready to self-excavate, all the kind of signs are telling us that this patient is agitated and hypertensive, tachycardic. All the other labs are within normal range. This patient has a history of withdrawal seizures, and what is the right agent in this setting? As much as we talked about benzodiazepines are an independent risk factor of ICU delirium, remember that there are some specific indications for which you need to use the benzodiazepine, and alcohol withdrawal is a very good example, and if you're not convinced, this is a very good infographic from the New England study from 2014 that really talks about you have to think about pain, agitation, and delirium all in kind of one picture and one setting, and if your patient is on medications that they may withdraw from, and alcohol is one of them, you have to address that as soon as possible. Now, this patient is appropriately managed, but goes home doing fine, comes back six months later after a car accident. At this point, we know that he doesn't have any alcohol on board. His wife told him that he's been sober, but he's in a lot of pain. He's agitated. We saw the other labs, and at this point, the question is, what might be the most appropriate agent? So, fentanyl infusion with the fentanyl intramenolases, an infusion for pain control, and again, this is from ICUdelirium.org, which is a very good reference talking about if your trauma is positive and your patient has a rash that is indicating agitation, you have to ask yourself, just like what we talked about, are they in pain first or not, and if they're in pain, which was the case in that patient case we talked about, you have to give them an NLG lift. Now, the patient's on a fentanyl infusion. The pain's under control, and then six days later, they're ready to extubate him, but it looks like he can't really be extubated because he's very agitated, and what do we do in this case? As we talked about, dexanitamidine might be the right agent because of the study that was published in 2016 talking about if you are using dexanitamidine versus standard of care, your delirium resolution may be faster, and your duration on mechanical ventilation might be shorter, and that's really where the guideline recommendation from 2018 is coming from as well. As far as antipsychotics, we talked about typical versus atypical antipsychotics. As you can see, typical, a good example is haloperidol. They're very strong dopamine antagonists. That's where a lot of those movement disorders come from, but then atypical antipsychotics not only have dopamine activity, but they have serotonin antagonism, and that gives them that better side effect profile for movement disorders, so they are less assistive with EPF or dysphagia and things like that, but it's important to note that routine use of these agents is not recommended, and then we'll talk about maybe when they will come into play. Here's a brief kind of table about the pharmacokinetics, the dosage, the route of administration, which might be helpful. Olanzapine, for example, is one of the atypical antipsychotics that comes in short-acting IV formulation. That might be helpful in acute education cases, and then here's a good review of side effects of these medications, and as you can see, some of these medications can be sedating. Quetazine is an example, and some may be associated with moderate risk of CPP prolongation, and Ziprafidone is a good example of that. Now, he's on dexamethamidine now. He gets transferred. He gets extubated. He gets transferred to the floor. His rash is zero, but he is a little bit bloated. He's uncomfortable. He's constipated, and then on the floor, he's confused, and he's kind of saying things that are not making a lot of sense. So what is the right kind of intervention here? Encouraging mobility would be the right answer here. Again, remember that we don't need to use atypical antipsychotics if we have a good reason for our patients to be delirious. Early mobility should be also focused on. Remember that this can happen even for people that are intubated, people who may be on pressers. As long as their hemodynamics and their respiratory status and neurological exam are stable, you can possibly mobilize them as early as possible, and this is just showing that even if your rash is negative 5 or negative 4, there are some passive ways to do that, but obviously, if you have a patient with rash of 0 to plus 1, you may have more opportunities for early mobility. Sleep, obviously, I can't say enough of this. We all have experienced that if you don't get enough sleep, you're at higher risk of delirium, and unfortunately, as much as we would love to have a drug that can help with sleep disturbances in the ICU, we don't have that agent yet. Melatonin has been studied with conflicting results. Dexmedetomidine has been studied with conflicting results, and it looks like non-pharmacologic is still the way to do. So, in summary, non-pharmacologic interventions are prepared for managing delirium, and dexmedetomidine is suggested for delirium in intubated patients where agitation is precluding extubation. Pharmacologic therapy is not recommended to prevent delirium, and we'll see that the typical antipsychotic is not recommended, but remember that you may be able to use them in acute agitation cases where there is safety concerns for the patient or the staff. These are the studies that I think may be helpful to look at, including the guidelines on how far this comes, and a little brief review of all these studies that, again, I think might be helpful for intensivists and non-intensivists. With that, I'm happy to answer any questions. Dr. Davis, is the fixed-dose, four-factor PCC approach specifically in the context of DOAC traversal evidence-based enough from your perspective compared to Warframe reversal, particularly in light of Anexa I research? I see. Thank you so much. So, unfortunately, we had all really hoped that Anexa I would have dove in to the dosing of PCCs a bit more heavily or utilized PCCs in a bit more of a robust way. Unfortunately, it was not an ideally designed trial, so I don't really turn to Anexa I as my answer. But there has been significantly more evidence published for fixed-dose for Warframe. So, I think it's pretty sealed the deal in terms of Warframe reversal utilizing fixed-dose. As far as fixed-dose for DOAC reversal, so at my institution, we are utilizing a fixed-dose strategy of 2,000 units. So, I do think it is still up in the air as to whether you should go weight-based versus the fixed-dose route. But to me, with the state of where evidence is at this point, I do think like it's reasonable to pursue a fixed-dose strategy, not in patients who are obese, just because those patients really haven't been examined as near as thoroughly or robustly. So, that's kind of my take on it. I'm still utilizing a max dose of no more than 5,000 units if you do decide to go the weight-based route. That's my take. There's still a lot more evidence coming out. Just unfortunately, it is all fairly low quality. Thank you, Dr. Davis. And the next question I'll ask both of you, Dr. Webb and Dr. Davis, for your reference for the medication dosing using body weight. Do you use actual body weight or ideal body weight? So, I can start with this question. And in terms of for status epilepticus, I think my approach, it certainly is going to depend on the agent, I think, to start. So, it's hard to kind of answer that question as a one-size-fits-all sort of scenario. But broadly speaking, I tend to err on the side of being more aggressive in patients in status epilepticus, and so usually will use actual body weight for my dosing. I think the caveats there is ensuring that you're keeping reasonable dose limits in mind. So, for example, phenytoin is a great example of a medication which has altered pharmacokinetics in the setting of obesity. And so, if you were to use a 20-milligram per kilogram dose without dose capping in a patient with morbid obesity, you'd likely get into the range of doses that will cause pretty profound cardiac toxicity. And so, in that context, I think the ESET trials maximum dose of 1,500 milligrams could be reasonable. There was a post hoc analysis of ESET which analyzed basically the likelihood of treatment response in patients with extremes of weight, which did not reveal any significant differences. Say in a patient who was 100 kilograms and only got 1,500 milligrams, that patient was just as likely to respond to somebody who was of a lower body weight. But basically, my point here being is if you do have a patient who is of extremes of body weight, and you're going to be giving a weight-based dose, it's important to keep in mind what the pharmacokinetics of that drug are in obesity. And if there are evidence-based caps in terms of reasonable dose limits, like from the ESET trial, I would use those. But for most medications, I would use actual body weight, not ideal body weight. Dr. Davis? For anticoagulation reversal, I'm using actual body weight to calculate all my medications. When it comes to status epilepticus, I take the exact same approach as Dr. Webb does, and being a little bit more thoughtful in terms of patients who are in extremes of body weight when it comes to dosing my ASMs. Great. Thank you. Dr. Webb, there's a question regarding clonazepam. Is there any available literature in this role for status epilepticus? Yeah, so that's a great question. So in Europe, clonazepam is available intravenously. And so there is data for clonazepam in status. I'll say I'm not extensively familiar with it, namely because we do not have intravenous clonazepam available here in the United States. However, clonazepam, as well as most other intermittent anti-seizure medications, have at least some support from a retrospective cohort perspective, meaning that if you are in a position where you've exhausted what little randomized control evidence you have, so you've given an appropriate upfront benzodiazepine, you've given an appropriate urgent therapy, you've then progressed to kind of a refractory treatment. At that point, you want to choose agents which make the most sense in that patient. And so what this is sometimes referred to as is rational polytherapy. For example, if you have a patient who's on levotracetam, leucosamide, and say, you know, third agent like parampanel or something along those lines, and every time they have a seizure, they respond extremely well to the initiation of a midazolam drip, that might be an example of a patient who responds well to a GABA-active agent. And clonazepam or clobazam is oftentimes what we use in practice here at MGH, may be the right choice for that patient. But once you get to those kind of fourth, fifth, sixth line therapies, the quality of the evidence is too low to definitively say whether one agent or another is the best choice for that patient. You really have to make that decision, keeping the individual characteristics of the patient in mind. Thank you. Talking about benzos, you did mention about IM midazolam. We have a question regarding the role of IV midazolam for seizure termination and status epilepticus, and are there studies comparing IV versus IM midazolam dosing or studies comparing IV midazolam versus IV clorazepam? Yeah, that's a great question. So I am not familiar with any high quality studies that specifically evaluate that question. There are at least a few registry studies which have looked at, you know, pre-hospital care in terms of route of administration for midazolam or other benzodiazepines. I think what I would say is the advantage of intramuscular midazolam is that you do get a slight depo effect, meaning that the duration of seizure activity may be slightly longer when you give it IM versus IV. And so, you know, I think some clinicians would say that if you have an IV, you really should use lorazepam just because it has that longer duration of anti-seizure activity. And so while IV midazolam shouldn't be as effective, really the downside is it has a closer pharmacokinetic panel or parameters to IV diazepam when given IV. And so it might not have a particularly long duration. So I think the real bottom line is that if that's all you have available, certainly that would be an effective agent. But I think in terms of the quality of the evidence, I don't think it's quite high enough to say one over the other is best. And so if you have an IV, you have lorazepam available, that's always going to be my go-to. But if all you have is an IV and say a patient has such low muscle mass that it's not feasible to give an intramuscular dose, then the IV midazolam would be a reasonable approach as well. Okay, thank you. And then regarding IV lorazepam, I think this was mentioned in several slides, regarding the dosing, is it four milligrams at a time with a maximum of 10 milligrams or eight milligrams? Do you mind clarifying the dosing of IV lorazepam administration? Yes, great question. So for the initial dose of a patient who's presenting with status epileptic, it's like the first dose of the benzo you're going to give that patient, 0.1 milligrams per kilogram, generally capped at four milligrams per dose is going to be that first-line therapy. If the patient's seizures persist and you need to administer another dose, you would give another four milligrams. The guidelines, whether it's between eight and 10 milligrams as a cumulative dose is generally what's going to be recommended. But that first dose should be four in most adult patients, and then you repeat another four if they're continuing to have seizure activity. Can you comment on a multi-pharmacologic use when a patient seems to require both, for example, both presidix and fentanyl or dexamethylamine? How would you approach patients that have features that may need two infusions or two medications? Yeah, I think, honestly, I think this is probably a case-by-case discussion, but the idea here is that, you know, in a lot of the cases, I think when we're adding dexamethamidine to fentanyl, the idea is that fentanyl may be at a very high dose, or we think that there is a component of agitation and pain. My goal and my approach in practice is to see if we could really figure out what is happening with the patient. If pain absolutely is the reason, you know, and we have started all the home medications, but we've thought about other things. Does the patient really need to be on dexamethamidine? And the other, you know, the opposite, I think, is true also. If we think that the patient is a little bit uncomfortable because the tube is there and we need to extubate the patient, and that's really the major part is that why are they on fentanyl? Can we get the fentanyl off and keep the patient on dexamethamidine and try to kind of, you know, help them with the extubation process? I think it's a matter of really getting to the bottom of what is happening. I think in real life, if someone's on both, my approach is that they're probably not ready to be extubated. There are other reasons happening, but I think ultimately, we need to simplify the regimen. And in every case, I think it's a little bit different. But I think trying to figure out what's happening and making sure that we're simplifying the regimen as much as possible, that would be my approach. But it's really hard to say which one should go because for every patient, that might be different. But I think ultimately, the goal and the hope for every patient in the ICU should be the minimum amount of sedation necessary. So however we can get our patients to the minimum amount of sedation necessary, I think that would be the approach. Thank you. For our last two questions, in reference to I think one of the cases, what if the intubated patient was already on dexamethamidine for a while? What would be your approach for that patient? Yeah, again, I think I know if they are, they are already on dexamethamidine, they're agitated. The question is, why is it that they're agitated, right? We know that dexamethamidine, there might be a little bit of a component of pain management with this drug, but it's not typically what we use for pain management. So if they're in pain, right, like thinking of hepatitis as the name suggests, pain first, agitation, delirium, immobility, and sleep, is it that they're in pain? If they're in pain, can we get their pain under control with hopefully intramenoboluses? Are they missing something on their electrolytes, or are they dehydrated? Are there nonforms that we can do? Again, I think really with delirium, the idea is that my approach is that, is there something we're missing that we have to approach first, as opposed to saying, oh, they're on dexamethamidine and it's not working. Let's give them a bunch of Haldol or let's sedate them more. I think the goal really should be, okay, if they're on dexamethamidine and they're still not being, we're not able to extubate them, what is this? Are they constipated? Are they retaining? Are they, metabolically, have we addressed everything? Are there home medications that we have not addressed? Are they withdrawing from something we didn't think about initially in the ED? So I think there's a lot to think about. I think, let's say if you address everything, right, you have a checklist and you're like, okay, I have gone through everything. They're still agitated, they're unsafe. If that's the case, and you know, you think your patient's unsafe or they're self-extubating, you really need something acutely for acute agitation. You could utilize one or two doses of either IV Haldol, obviously their QTP is under control and there is no drug-driven interactions, no contraindications, or IV Olanzapine. But I think, again, I think the theme here is pain first, agitation, delirium, and less is more when it comes to ICU delirium. Thank you. For our last question, is there still evidence against patient getting Benzodiazepine within a close period since last administration of Olanzapine IM? So sorry, just to make sure I understand the question, is there a contraindication for giving Benzodiazepine if they've already received atypical antipsychotics, is that? Yes, intramuscularly, yeah. Okay. So from the last administration of Olanzapine and they give a Benzodiazepine within a short period of time, is there evidence against that? I mean, I don't think that there is, you know, black and white evidence saying if you've done IM Olanzapine, you shouldn't do, or if you've done IM Benzodiazepine, you shouldn't do IM Olanzapine. I think the question is, again, how are they looking like hemodynamically? How are they looking like from the neuro status and things like that? But I think as far as if I'm understanding the question correctly, as far as administration time and route of administration back to back, I don't think there is black and white. I think the question is that are they hemodynamically stable and is this a safe approach from, you know, the typical ICU care, airway, hemodynamics, things like that. Okay. Thank you so much. I think that's all the time that we have. That concludes our Q&A session. Thank you, Drs. Davis, Dr. Webb, Dr. Farrokh, and thank you to the audience for attending. Again, this webcast is being recorded and the recording will be available to the registered attendees within five to seven business days. Log into mysccm.org and navigate to the My Learning tab and click on the neuropharmacology course. Click on the access button to access the recording. That concludes our presentation today. Thank you again.

neuropharmacology

anticoagulant reversal

status epilepticus

ICU delirium

Nicole C. Davis

Andrew Webb

Salia Farouk

benzodiazepines

anti-seizure medications

evidence-based strategies