Hello, my name is Nicole Davis and I'm the Neurocritical Care Pharmacist at the Mount Sinai Hospital as well as faculty at Toro College of Pharmacy. Today we're going to be reviewing pharmacotherapy relevant to the care of neurocritically ill patients. Some of the topics that we'll cover today are some of my favorite topics to cover when it comes to caring for neurocritically ill patients. So we'll talk about anti-epileptic drugs that are high risk for drug-drug interactions, we'll talk about anti-platelet drugs, and we'll briefly touch on vasopressors as well as sedative agents that include opioids and non-opioids, and then finally we'll wrap up with appropriate antibiotics for intraventricular administration. So I like to start off with the anti-epileptic drugs because these drugs are always going to be seen in a neuro-intensive care unit. A lot of these drugs, they do come with a lot of drug-drug interactions, so you kind of have to consider that when you're managing your patients, ranging from seizure prophylaxis all the way to status epilepticus management. So our first generation AEDs that include phenytoin, phenobarb, valproic acid, they all have a lot of inter-individual variability, so in critically ill patients they may have various kinetic factors that could be altered as listed for you on the screen. Additionally, you have to consider that outside of kinetic factors that could be altered just based on critical illness, some AEDs can alter the kinetics of other AEDs and even of themselves. So these include drugs that we call inducers, that they induce the kinetics of other AEDs, could be inhibitors where they inhibit kinetics, or you have drugs like carbamazepine that actually have auto-induction where they'll induce their own kinetics. So as you add on more and more drugs to a patient's profile, multiple drugs can lead to unanticipated drug interactions as well as adverse drug events. So we will divide these interactions into both pharmacodynamic and pharmacokinetic interactions. So pharmacodynamic interactions include medication combinations that cause additive or antagonistic effects. So for an example, warfarin and aspirin when you combine them will increase the risk of bleeding though they do not directly interact, and then drugs like valproic acid and topiramate when combined can lead to increased risk of hyperhormonemic encephalopathy. We also consider pharmacokinetic interactions, so this is where different drugs could cause alterations in another drug's absorption, its distribution, metabolism, or elimination. So all of these things we do consider when we're assessing for drug interactions. So this looks like a bit of an overwhelming picture, but it is one of my favorite pictures that kind of describes all the various mechanisms of actions that we have for our various AED drugs. So it ranges from a lot of drugs blocking sodium influx like phenytoin, glucosamide, lamotrigine, blocking calcium influx, blocking glutamate receptors, and so on and so forth. So please review this slide for just a brief overview of the various mechanisms that we have available to us. So let's start out with one of the more common, but maybe slightly more difficult AEDs to manage, phenytoin and phosphenytoin. So speaking about its PKPD, it has a half-life of around 6-24 hours when its concentration is below 10 mics per ml, though this half-life will increase with increasing concentrations. A lot of the drug interactions that you get with phenytoin are related to its CYP enzyme metabolism, as well as the CYP enzymes that phenytoin will induce. So it's metabolized by 2C9 and some 2C19, but it will induce CYP3A4, 1A2, and UGT. The other place that you can get some drug interactions is as it relates to phenytoin's protein binding. So it's protein bound around 87-92%. So in your patients that have low albumin, you actually have to correct phenytoin's concentrations utilizing the Winter-Tozer equation or sending a free phenytoin level. And then in your patients that have renal failure, even though phenytoin is not renally cleared, you have to take into account the decreased protein binding that could lead to increased concentrations. So we have two ways that we can give patients phenytoin, essentially. We can either give them phenytoin via IV or oral route, or you can give them the prodrug of phenytoin, phosphenytoin, which you can give IV or IM. It has a little bit more stability in NS and D5W, but the really nice thing about phosphenytoin is that you can give it three times faster than phenytoin. So you can try to minimize some of the cardiac toxicity that you can get if you administer phenytoin too fast. Phenytoin and phosphenytoin are monitored via levels, so there's two ways that you can do this. You can either check a post-load level, so that's just making sure that you've given enough phenytoin if your patient's actively seizing. So you check that level one to two hours after your load, and your goal is around 20 or so. So if it's not, if you haven't reached an appropriate level, you can re-dose with five to 10 mgs per kg. Steady state will occur in three to five days after you load, so once you reach steady state, that's when you shift over to trough monitoring. So with trough monitoring, you want to check a level 30 minutes before your next dose, and that's to ensure that your patient's both not getting toxic, but also getting enough phenytoin that it's going to be efficacious. You do get dose-dependent adverse effects with the various levels, so as your levels increase past what we would typically cut phenytoin off at, so around 20, you start to see more adverse effects. So it can range from nystagmus to ataxia, and then some of the worst ones that you may see could be coma. Phenytoin can also induce seizures, so that's something to watch out for, especially if you gave way too much phenytoin or your patient's albumin is really, really low and you didn't account for its protein binding. And then if it is high enough, it can lead to patient's death. Very briefly, I do want to touch on the correction factor that you can use to correct phenytoin in the settings of low albumin. So phenytoin, as we mentioned, very highly protein-bound. So when you have patients who have low albumin, you have to account for the fact that the patient may actually have more unbound phenytoin that's going to cause a pharmacologic effect. When it's bound to albumin, it's not going to do anything, so it's that unbound portion that we care about. So you do have to utilize the Winter-Tozer equation to account for low albumin states, or you can send a free phenytoin level, though most hospitals don't have this level able to be run in-house. So it does require a send-out to LabCorp or some other lab, and it's usually a turnaround of four to five days. So not really helpful if you really suspect your patient's toxic. So you can just Google phenytoin correction. It comes up. Just be aware of what equation that you're using and the correction factors. There has been a couple studies that looked at the various correction factors and if it actually correlates with free phenytoin levels. A little outside the scope of this talk right now, because I could really talk about it for a few minutes, but if you have normal renal function, you can use any of the correction factors I have on the screen, or if you have renal failure, then you're going to use a lower correction factor. If patients have both hypoalbuminemia and renal failure, unfortunately, this equation doesn't actually correlate at all to free phenytoin levels. So in that case, you do have to try to send a free phenytoin level and use your best judgment as far as the levels go. Because phenytoin is hepatically cleared, you can expect it to have some SIP-mediated drug interactions. So on this slide and on the subsequent slide, I've listed some common drugs that you may encounter in your ICU. So instead of memorizing every drug interaction that can occur with phenytoin, what I recommend doing is anytime you have a patient on phenytoin, utilize a drug interaction checker. Your pharmacist can do this for you, or you can utilize the tool in Lexicomp or in Micrometics just to assess that all the medications you have your patient on, that they're not interacting in a way that you're not going to expect. On the previous slide, I listed a lot of drugs that will have some type of impact on the concentration of phenytoin. On this slide, phenytoin will have some type of impact on all of the drugs listed here for you. A takeaway that I do want you to remember, and that's good to commit to memory, is phenytoin will always have some type of effect on oral anticoagulants. So it'll decrease the concentrations of our DOACs, like apixaban, dabigatran, and rivaroxaban, and it can increase concentrations of warfarin, so you can see increased INRs. So keep in mind whenever you do need to anticoagulate a patient and they're on phenytoin, you may need to do some additional monitoring. So switching gears to valproic acid, it has a half-life of around 9 to 19 hours, and like phenytoin, it's metabolized extensively hepatic via glucuronide conjugation, but then it also has some 2C9, 2C19, 2A6, and some 2B6 metabolism. The other thing that valproic acid can do is it can inhibit the enzymes 2C9 and 3A4, so drugs that require 2C9 and 3A4 for their metabolism would then be inhibited by valproic acid. Valproic acid is also highly protein-bound, like phenytoin, so 80 to 90%. So when we're talking about its free fraction, depending on what its concentration is, you'll have increasing free fraction of valproic acid to exert its pharmacologic effect. For its dosing, you give a loading dose followed by maintenance dosing. So you give a loading dose of about 40 mg per kg, and a maintenance dose will range from 15 to 60 mg per kg per day, and you split that up into different frequencies based on the formulation that you're giving. So if you're giving IV or immediate release valproic acid, you dose it Q6, so every 6 hours. If you're giving delayed release products, you dose it every 12 hours, and extended release products will be dosed every 24 hours. So valproic acid is another drug that we'll monitor via levels. Typical monitoring will occur via trough levels, and we'll target concentrations of around 50 to 100 mg per ml. If you have hypoalbuminemia because it is highly protein-bound, this can lead to increased free levels, so there are times where it may warrant sending a free level. It does have drug interactions with phenytoin, so valproic acid may actually increase or decrease the activity of phenytoin kind of unpredictably. It can displace phenytoin from its protein binding, so then you'll have an increase in free phenytoin concentrations, which can increase risk of toxicity, but then it can also inhibit the metabolism of phenytoin, leading to a decrease in total concentrations. So phenytoin can then also actually decrease valproic acid concentrations, so there's almost like a dual drug interaction happening here. Likely it's due to induction of metabolism, but then it could also lead to an increase of hepatotoxic valproic acid metabolites. So I actually try to avoid administering these drugs in the same patient. So valproic acid is associated with various side effects, so they can range from sedation, ataxia, and tremor. These are usually dose-dependent, so if you decrease the dose, sometimes you can manage this. It is also associated with hyperammonemia. This is a dose-independent side effect. You can also have hepatic side effects, so you can have ranging from increases in serum transaminases to fulminant hepatitis. The other takeaway from here is that valproic acid can inhibit the metabolism of phenytoin, phenobarbital, lamotrigine, and lorazepam. So those are other AEDs that could be used in conjunction with valproic acid. Be careful if you're going to have to give warfarin with valproic acid, as valproic acid is an inhibitor, so you can see increased INRs. And then if you have to give a carbapenem to your patient and they're on valproic acid, you absolutely have to take some steps to address that, as the carbapenem will drive valproic acid concentrations down to zero. You can't increase the valproic acid to overcome this, so you either need to switch antibiotics or you need to switch AEDs, just because you cannot give them in conjunction. Switching gears over to levotracetam and leucosamide, these drugs are a lot easier to use than phenytoin and valproic acid. They don't have any drug interactions, no CYP enzyme metabolism, or very little CYP enzyme metabolism. They're not protein-bound, so with that being said, they are renally cleared, so you do have to adjust for that in renal dysfunction, and then if patients are getting dialysis, you do need to give extra doses of dialysis as it can be cleared. We are utilizing weight-based dosing of levotracetam, which was probably discussed in the ESSIT trial in a previous lecture. You don't really need to monitor levotracetam either. We really only utilize levels if you're concerned about toxicity or if you're trying to assess for your patient's compliance. In terms of its side effects, very well-tolerated, might get some somnolence or possibly agitation or behavioral changes, though if you utilize briviracetam, that's thought to be a little bit less with that drug. Same thing with leucosamide, very easy to use, kinetics very straightforward, minimal metabolism, so you really don't get too many drug interactions. Again, we don't monitor leucosamide levels, only utilize it for assessing if they are compliant or if you're concerned about toxicity. One of the adverse effects that you could see with leucosamide, though it's thought to be very, very rare, is that it could be associated with a very brief prolongation of your PR intervals, but it's not known to be QT prolonging, so just monitor for AV block or a possible bradycardia. So on this slide is an example of a patient that I've seen pretty frequently throughout my time in the neuro-ICU, so it's a patient who's high risk for drug interactions, they're experiencing status epilepticus, they need an AED. So on this slide, please read through this case and kind of think about, you know, how would you manage this patient based on his risk for drug interactions and his risk for side effects. Let's talk about antiplatelet drugs now. So the neuro-ICU is really starting to see a pretty significant increase in the use of these drugs just through various IR procedures where patients get some type of stent placed or they've had a thrombectomy and have required some type of stent, or even post-stroke patients will now get antiplatelet agents. So this is another classic picture that represents platelet activation. So platelets are activated via many different mechanisms. We do have a couple different classes of drugs that can inhibit a handful of these mechanisms. So it ranges from aspirin, which inhibits COX-1, which will then inhibit the production of thromboxane A2. We have our P2Y12 drugs that will inhibit the P2Y12 receptor that will decrease platelet activation. And then finally, we have our GP2B3A inhibitor drugs that prevent the final activation pathway of a platelet. So the P2Y12 receptor inhibitor class has some of the newer antiplatelet drugs available. So there are two different types. There's clopidogrel and prasogrel, which are both prodrugs, so it does require some activation via CYP enzymes to become an active drug. And then we have ticagrelor and cangrelor, whereas these drugs are already completely active, they don't require activation. So as soon as you give them ticagrelor orally, cangrelor via IV, it'll start to have an effect a little bit faster than clopidogrel and praseugrel. So as I said, with clopidogrel and praseugrel, kind of similar in its pharmacokinetic, so they are both irreversible receptor binding. Steady state maximum inhibition of platelet aggregation a little bit less with clopidogrel and praseugrel as compared to ticagrelor and cangrelor. It does require some activation as we talked about and has an offset of around five to seven days because it is irreversible. The one thing to be said about these two drugs though is they are dosed only once daily. Ticagrelor is our reversible oral P2Y12 receptor inhibitor. It's time to maximum inhibition of platelet aggregations around two to four hours, has an offset of around three to five days, does need to be taken twice daily. Cangrelor is the newest P2Y12 agent on the market. It is a reversible antiplatelet agent, has a steady state inhibition of around 95 to 100%, so extremely potent and then works very, very fast. So we'll have extreme potency in around two minutes or so. Has an offset of around 60 to 90 minutes and it's given via a bolus followed by a continuous infusion. It is rapidly inactivated by dephosphorylation. So when you turn the drip off, it'll actually start to become metabolized away. And then it's not renally cleared so you don't need to worry about renally dose adjusting. I provided the dosing for you in this chart. Keep in mind that there is a significant drug interaction between Cangrelor and Clopidogrel and Prasugrel. So they both bind to the same place on the receptor. Cangrelor has a much higher affinity for that receptor. So if you continue the drip in the background and then give an oral agent, that oral agent will actually just kind of hang out in the serum, not bind to the receptor and become metabolized away. So when the Cangrelor is finally turned off, you don't have as much oral drug there to take its place. So don't administer them at the same time. Turn your drip off and then administer Clopidogrel or Prasugrel. Ticagrelor is different. It binds to a different place on the P2Y12 receptor. So technically you can give Ticagrelor and Cangrelor together at the same time and it will still be safe for your patient. Switching gears over to eptifibatide and Tirofiban. So these are two options for GP2B3 receptor inhibitors. They are IV only and very potent antiplatelet agents. They do require a bolus dose and then are followed by a continuous infusion. So I have the dosing here on the screen for you. Their half-life is considered to be fairly long, especially when you compare it to Cangrelor. Eptifibatide has a half-life of around two and a half hours, Tirofiban, a half-life of around two hours. Its onset is very fast though. So within five minutes, you have 80% platelet inhibition with eptifibatide, around 90% within 10 minutes with Tirofiban. And then that inhibition will last around four to eight hours so when you turn the drip off, just keep in mind, it's gonna hang around for just a little bit. And then they both are renally cleared. So if you have a patient that does have some type of renal dysfunction, you need to adjust the dose. And then if they have ESRD when our dialysis dependent, really need to avoid these agents. So we actually use eptifibatide and Cangrelor at my institution. So it kind of varies. Most of the providers are more familiar with eptifibatide and will use that agent. But Cangrelor is kind of nice because it doesn't require renal dose adjustments if you have a patient that has renal dysfunction at baseline, Cangrelor is gonna be kind of more preferred. And then we've also started using more Cangrelor because it's kind of thought that maybe Cangrelor might have a little bit less bleeding and might be a little bit more safe for our patients. So we are starting to kind of study that and hope to get a publication out soon about that. So let's talk about vasopressors for just a moment. Another very, very commonly used class of drugs in the neuro ICU. Again, a very common chart that relates to the pharmacology of our various vasopressors. The only thing that might be a little bit new for you is now angiotensin II is being added on. So I don't actually have this vasopressor available at my institution, but it could be available at an institution that you practice at. So starting with dopamine, again, everyone is probably kind of familiar now that it has various receptor activity at varying levels. So as you increase your concentrations of dopamine, you start to hit other receptors. So first you'll start with dopamine receptors, followed by hitting your beta receptors and then alpha receptors at high doses of dopamine. Epinephrine and norepinephrine, primarily alpha. Epinephrine does have more beta activity. Norepinephrine has a little bit of beta, more beta one than beta two. Phenylephrine is our alpha only vasopressor. And then some of you may be familiar actually with mitadrine as mitadrine has kind of been kind of a popular option at the past few years, even though the MIDAS trial may have something to say about that. But again, alpha only. We have vasopressin, which will hit our vasopressin receptors, so our V1 receptors to help augment blood pressure. And then finally we have angiotensin II, which will augment our RAS system leading to vasoconstriction and some aldosterone release. The dosing is provided for you in this chart as well. Though the dosing, you know, will vary in terms of what the theorized max dose is at various institutions. And your institution may utilize weight-based versus non-weight-based infusions. So just kind of keep that in mind when we're talking about dosing. So this chart will list out for you the various pharmacodynamic effects all the vasopressors will have, ranging from SVR to MAP to cardiac output, heart rate. So please review that if you're not necessarily familiar. Something that I did include because this is a neurocritically ill discussion, I did want to talk about some of the CNS effects that we'll see with our vasopressors. So dopamine's, you know, not really thought to cross the blood-brain barrier. Epinephrine, norepinephrine, also has pretty poor penetration of blood-brain barrier. It has limited vasoconstriction of the cerebral arterioles. Same thing with phenylephrine. Vasopressin, interestingly enough, can increase adrenocorticotropic hormone release via the V3 receptors, so some possible effects there. And then angiotensin II, some literature has indicated some possible blood-brain barrier disruptions and neurotoxicity related to angiotensin I receptor activation. I haven't come across a study with angiotensin II in neurocritically ill patients, so this is just kind of more of a theorized possible mechanism. Going through peripheral safety, so dopamine, epinephrine, norepinephrine, phenylephrine can all be utilized peripherally. Just utilize caution, make sure you're using the biggest vein possible and that nursing is monitoring it appropriately. Vasopressin and angiotensin II probably should not be administered peripherally. And then some notes. So with dopamine, not really a vasopressor of choice. I'm sure someone discussed the SOAP2 trial in the shock lecture. With epinephrine, you can see increased serum lactate and glucose, so when you see an increased lactate and they're on an epinephrine infusion, some of it could be related to the epinephrine. Norepinephrine from the SOAP2 trial, we know it has less arrhythmia compared to dopamine, probably has a little bit less arrhythmia compared to epinephrine just because it has decreased beta activity. For phenylephrine, patients can experience some autonomic dysfunction and they may experience some exaggerated effects from phenylephrine. With vasopressin, because it might have some type of stimulation via the V3 receptors or maybe it's another mechanism, but some animal studies, and then there's been a poster that's described this in humans, but vasopressin may be associated with increased rates of vasospasm post-subarachnoid hemorrhage. So we will not use vasopressin infusions in our subarachnoids in my unit. And then like I said before, angiotensin II, can't find any data in neuro-specific indications, but just to keep that in mind. All right, quickly reviewing a couple of drugs that we utilize commonly in the neuro ICU for pain and sedation management. So this is a pharmacology slide that discusses our IV opioid options. So this chart is essentially taken from the PATIS guidelines. So if you want more information on these particular drugs in terms of its pharmacology, I do recommend reviewing the 2013 and 2018 PATIS guidelines. So all four of the agents listed for you on the slide, we give via continuous infusion, and we can use them in our neurocritically ill patients. Though morphine, we do try to avoid just because it can accumulate in renal dysfunction, and some of its metabolites are associated with neurotoxicity. You can also see myoclonus with morphine drips. So we tend to really avoid using them. Other things to watch out for with fentanyl and remifentanyl, you can actually see chest wall rigidity with bolus doses. They do have some organ independent metabolism, so they can be nice to use because they're very short acting. But keep in mind, all of your opioids can lead to respiratory depression, delirium hallucinations. They don't have any amnestic effects. So if you're having to paralyze a patient, you need to make sure you have another sedative on board. So with the opioid pandemic ongoing, there's really, we have a lot of options now for non-opioid pain management. So first I want to talk about ketamine as ketamine is kind of one of my favorite drugs to use because we're getting all kinds of new indications for ketamine. We've started using it in status epilepticus, and it's been working really nicely. So we can utilize it for pain management. It's given via bolus dose or maintenance dosing. It does have a catecholamine release, so that's why you kind of see maybe increased blood pressure but keep in mind sometimes that once you deplete all your patient's catecholamines, it can become a little bit of a negative inotrope. It has anti-NMDA activity that's favorable in status epilepticus. And then the other takeaway is it is safe to use in neurocritically ill patients. The ICP raising effect has been debunked at this point, and it can be associated with beneficial hemodynamic stabilizing effects. Acetaminophen, really nice because it doesn't have any effect on your neuro exam. It's opioid sparing, but can be hepatotoxic, so just be cautious of that. NSAIDs, again, no effect on the neuro exam, but it has been associated with some nephrotoxicity and possibly increased bleeding. So we're pretty selective about the patients that we'll give NSAIDs to. Gabapentin and carbamazepine, both options for neuropathic pain. They are both also AEDs, so it's kind of nice to have that anti-seizure property in neurocritically ill patients. But carbamazepine is associated with a lot of drug interactions, and you have to titrate it to avoid hypersensitivity reactions, so we tend to avoid carbamazepine in these. So these are the sedative options that we have, lorazepam and midazolam for our benzo options. Lorazepam we don't really use just because the risk of propylene glycol toxicity with the infusion. And then propofol, definitely our most popular sedative agent, and then dexmedetomidine, which also has its role in ICUs. So a lot to take away from this chart. I did provide the dosing for you. Again, refer to your own institution guidelines for more guidance. So other things to discuss. So we do try to avoid midazolam infusions for sedation. Now we will use plenty of midazolam for status epilepticus, but the reason we avoid it for sedation is it will accumulate, and that will lead to delayed awakening. So whenever we're trying to get a neuro exam, really difficult if they've been on midazolam for long periods of time. Again, don't really use lorazepam anymore because of propylene glycol. With propofol, definitely our most popular agent to use for sedation. Keep in mind, propofol does not have any type of analgesic properties to it, so you're not gonna get any pain management, so you need to administer it with some type of opioid or non-opioid pain management option. It is lipophilic, so it does have some calories associated with it. And then it's thought to be neuroprotective, has a little bit of anti-NMDA activity to it, as well as GABA activity. So you can depress seizure activity and lower ICP with it, so that's really nice. And then when you turn the drip off, patients will wake up pretty quickly, so you can have neuro exams pretty fast. Dexmedetomidine, nice because it doesn't have any type of respiratory depression, so it's good for patients who are not intubated and need some type of continuous infusion, just because they're very anxious or getting agitated. We can also use it to decrease the shivering threshold, and then it's also associated with faster recovery for neuro exams, but just be aware it has been associated with some withdrawal-like effects. And now to wrap up the pharmacology lecture, just wanna touch on intraventricular medications. So we have many ways to administer medications to a patient. One of the ways we're talking about today is intraventricular administration. So the reason that we'll administer drugs directly to the ventricles is because the blood-brain barrier will actually prevent some medication from entering, especially a lot of antibiotics. So if we have some type of CNS infection, sometimes administering the antibiotic directly to where the infection is occurring can help with the treatment and the management of that infection. So while it's great that we can bypass the blood-brain barrier and maximize that concentration at the site of the infection, unfortunately, the literature is kind of variable on rates of success. If you're utilizing the intraventricular methods, it's something to kind of keep in mind. Whenever we're administering medication to the ventricles, we wanna make sure we administer it utilizing an isovolumetric technique. So if you're administering less than 10 mLs, you want to make sure you're administering more than 10 mLs. You probably don't need to remove CSF, but if you're instilling more than 10 mLs of medication, it is recommended that you remove an equivalent amount of CSF to accommodate that. So this is a great discussion to have with our neurosurgical colleagues. And then the dosing may be variable dependent on the ventricle size, as well as the amount of drainage that's coming out of an EVD or other type of drain. Whenever you administer your medication, you wanna clamp your drain for about 15 to 60 minutes just to allow for CSF equilibration. And then you want your medications ideally to be preservative free as preservatives can kind of irritate the ventricles and the brain matter. All right, this slide for you lists out a lot of medications that we can administer intraventricularly, and the dosing is here for you. So this is all what's recommended by the IDSA. And then I do have some side effects to watch out for. A lot of the side effects include epileptic activity potential. So that's kind of unfortunate, but unfortunately it just is part of administering these medications that can irritate the brain. You can also see mental status changes, meningeal inflammation, so almost like an aseptic meningitis picture. And then you can also see other type like neurotoxicity, possibly Parkinsonian symptoms with amphotericin. So just be cautious and make sure you're really selecting your patient appropriately if you're gonna give them intraventricular antibiotics. All right, I wanna thank everybody for listening to my talk. I know we covered a lot of material very, very quickly, but I hope, like I said, everyone was able to take something away, whether it was drug interactions, whether it was some vasopressor, CNS penetration, or antibiotic dosing for intraventricular administration. Again, thank you so much.

pharmacotherapy

neurocritically ill patients

anti-epileptic drugs

anti-platelet drugs

vasopressors

sedative agents

intraventricular administration