SCCM Resource Library-Emerging Practices and Updates in Neurocritical Care: What an Intensivist Needs to Know

Video Transcription

Thank you so much for this opportunity to present on status epilepticus and seizures in the ICU, the shakes and bakes in the ICU. I'm Neeta Gayage.  I'm a neurointensivist from the Icahn School of Medicine at Mount Sinai in New York, New York.  I have a few disclosures, none of these are relevant to the content that we're going to talk about today.  So the objective of today's presentation is to talk about the latest clinical consensus and guidelines of the management of seizures and status epilepticus in the ICU.  So let's jump right in. What are seizures? Seizures are essentially transient occurrences of signs or symptoms related to abnormal synchronous discharges of neuronal activity.  They account for about 1 million or so visits to the ED, about one in every 10 patients is going to develop a seizure in their lifetime, and about 1% of these patients will require  to be intubated. Seizures with respect to their duration, so brief seizures are categorized as seizures  that last for less than five minutes, prolonged seizures between five to 30 minutes. Status epilepticus, the definition, according to the American Epilepsy Society, is a definition  that I have highlighted here in red. And in the next slide, we're going to talk about a more clinically relevant definition that was endorsed by the Neurocritical Care Society.  In convulsive seizures, they're typically self-limited, and very rarely are they going to end up becoming prolonged if they're going to self-terminate.  Definitions by status epilepticus can be characterized as seizures that last for five minutes or  longer, or recurrent seizures without any return to a patient's baseline between seizures,  or continuous clinical or electrographic activity if that patient's been connected to continuous EEG monitoring.  Typically status epilepticus is characterized as those that are treated with at least two  appropriately dosed anticonvulsants and super-refractory persistent seizures despite 24 hours of continuous IV, third-line medications such as Versed, propofol, ketamine, et cetera.  And those seizures that come back as these third-line agents are being down-hydrated. So historically, although the definition does say patients continuously seizing for 30 minutes,  typically, if ever, is anybody going to allow their patients to continue seizing for 30 minutes?  For convulsive status epilepticus, there's a clear failure of the brain to inhibit this abnormal synchronized activity.  Occurs in about 6% of patients who are presenting to EDs, and in the United States alone, the burden of status epilepticus for patients getting admitted to the EDs is upwards of  150,000 patients. Seizures will become self-sustaining after 30 minutes, so time truly is brain.  In terms of the pathophysiology of seizures, so GABA, which is predominant inhibitory neurotransmitter,  those receptors for GABA get down-regulated or decreased when a patient is seizing. And the excitotoxic neurotransmitter, glutamate, the receptors for glutamate, the NMDA receptors,  get up-regulated. This particular slide is meant to highlight why time is brain in status epilepticus, and  why is it so important to recognize seizures early and terminate these seizures early so that they don't propagate and your patient doesn't develop status epilepticus.  So as we look at an acute seizure, so we said that most of these brief seizures are going to be less than five minutes or so. So under two minutes, there's an acute seizure.  Earlier impending status as the seizures continue for about 10 minutes, established status epilepticus  by the time someone's continued to seize for about 30 minutes, refractory status, so not responding to appropriately dosed AEDs.  And then this malignant status epilepticus or refractory status epilepticus can then continue for days. And why is that going to happen?  That is going to happen specifically because initially there'll be a failure of inhibition,  but your patient is still going to be responsive to GABAergic agents such as benzodiazepines.  And when there's excessive excitation, then your patient's going to become GABA unresponsive.  So recognizing seizures early, treating early will lead to the termination of seizures and prevent the propagation to status epilepticus.  What are some common etiologies of status epilepticus? So specifically looking at distribution between adults versus children, you'll notice that  in children, infectious etiologies tend to be the most common cause and in adults, perhaps noncompliance in those patients who have a known diagnosis of epilepsy, noncompliance  with their medications tends to be a common cause. Why are seizures harmful? So seizures can cause multisystemic effects right from elevated brain temperature and  thereby leading to increased metabolic demand, vascular injuries or cardiac effects such as arrhythmias, pulmonary.  We know that patients can hyperventilate, aspirate and are going to require mechanical ventilation and others such as acidosis, rhabdomyolysis, hyperglycemia.  And another way of thinking about the complications of status epilepticus, about 20 to 40% patients  are going to then develop epilepsy at a neurologic level, of course, hypoxic ischemic encephalopathy  or hypoxic ischemic injury, excitotoxic brain injury, cerebral edema, increased ICP, cardiorespiratory problems and metabolic problems. Clinical signs.  So convulsive seizures, convulsive status epilepticus is much more easier to recognize because you can see what's happening to your patient.  Nonconvulsive, more difficult to recognize because there may be very subtle clinical signs or there may be no clinical signs.  So unless you've connected a patient to continuous EEG monitoring, you may not be able to identify patients with nonconvulsive seizures or nonconvulsive status epilepticus.  In terms of the guidelines, the Neurocritical Care Society guidelines from 2012 and then the American Epilepsy Society guidelines from 2016, they're very similar with respect to  several of the recommendations that they make. In terms of the principles of management of status epilepticus, of course, like any  emergency, ABC is always going to come first, symptomatic treatment of the seizures themselves  as you're simultaneously, you've got to parallel process, so simultaneously identifying the  underlying cause for those seizures, preventing secondary neurological injury and prognosticating and enabling your patient to embark on the trajectory towards recovery.  So when we think about time as brain, the stabilization phase can last from the first, as you start the clock, zero to five minutes, you're going to stabilize your patient.  So assessing every breathing and circulation, does my patient need to be intubated or not? What are my induction agents going to be?  If you're suspecting status epilepticus, it's wise to use either Versed or Propofol as your induction agent. Similarly, you could also use ketamine as your induction agent.  Time from seizure onset, we're going to monitor the vitals, assessing oxygenation and getting a finger stick, and then also trying to obtain labs as you're getting access in.  The initial therapy phase from five to 20 minutes, choosing the right agent, the right dose, and administering the dose in a timely fashion is going to be very important to try  to terminate the seizure from becoming status epilepticus. So in terms of the dose for IV lorazepam, 0.1 milligram per kg per dose up to four milligrams.  So typically I'll end up using four milligrams as my first dose, another four milligrams as my second dose.  By the time I'm reaching for my second dose, I'm going to think about intubating my patient. And at the same time, if it's somebody who is not an average size adult, or they have  preexisting hepatorenal dysfunction, I'm going to be more careful as I think about administering a second dose of lorazepam or Ativan.  It's important to not use incremental doses like one milligram, followed by two, followed by three, because that's going to lead to more respiratory depression rather than help  in terminating your seizures. So try to hit your patient hard and fast to prevent status epilepticus.  And the other medications that you could use is IM, IM midazolam, and we will talk about the Rampart trial in just a brief moment.  The second therapy phase that lasts from about 20 to 40 minutes, you're going to choose your second line agent.  That second line agent could be IV phosphonatone, valproic acid, IV leptoracetam, or IV penobarb.  And these are some of the doses that have been recently studied in the ESET trial, specifically for dilantin, for valproic acid, and leptoracetam.  The third line therapy, or the third therapy phase, which lasts from 40 to 60 minutes, there's really not very good evidence to guide this particular phase.  And the data for this phase comes from mostly retrospective studies or from registries. So thinking about which anesthetic agent or which continuous IV infusion you're going  to use is going to be of paramount importance, whether you're going to use midazolam or you're going to use propofol or ketamine, and how do you choose between these and what your  doses should be. One key thing to keep in mind, by the time you're reaching for your third line agent, you have to ensure the patient is going to become hemodynamically unstable.  And making sure that you have pressers ready at the bedside before you start introducing  some of these will prevent your patient from coding and developing any secondary neurological injury.  So now let's look at some of the evidence for where do we get the evidence for some of these recommendations.  So specifically looking at the pre-hospital phase, when there's no IV access available,  the Rampart trial study, this was a non-inferiority study, the pre-specified non-inferiority margin  was 10%, and this trial met that. And also ended up showing superiority of IM midazolam over IV Ativan.  So IM midazolam doses was 10 milligrams or 5 milligrams in this particular trial, and it met its primary efficacy points. This study recruited both adults as well as children.  In the pre-hospital treatment phase, of course, getting the vital signs, ABC, positioning,  trying to parallel process, asking another team member to gather history to better understand what the potential underlying cause for the seizures and potential status epilepticus  is going to be, getting a point-of-care glucose testing, and potentially trying to establish IV access. Again, it's not important to try to get this IV access right away.  It's also very well to IM midazolam and ED activation by EMS to take this patient to the nearest ED.  The VA cooperative study from 1998, classic paper that looked at the first-line agents, lorazepam versus diazepam, dilantin versus phenobarbital.  And from this particular trial that recruited 570 patients with overt generalized convulsive status epilepticus, we see that IV lorazepam at 0.1 milligrams per kg is an appropriate  first-line and very effective first-line agent. More recently, the Eclipse and Concept studies, both in pediatrics, compared Keppra versus phenytoin.  What should be your first, second-line agent?  Found that they're both equally efficacious, and you could choose to do either. And specifically looking at ESET, which is, again, another landmark trial in status epilepticus  management, compared levatoracetam, valproic acid, and phenytoin. And what we do get, another key point that we get in this well-conducted randomized controlled  clinical trial, that's 60 milligrams per kg of levatoracetam. So prior to this trial, I think a lot of us were very likely underdosing levatoracetam,  and we were choosing it as our second-line agent. So choosing the right dose, 60 milligrams per kg, and a maximum of 4,500 milligrams, all these three are comparable.  So whatever you have available, make sure you choose the right dose and you choose it early enough to prevent your patient from going into refractory status epilepticus.  And in terms of the basics, of course, as we move into this phase where your patient is in the hospital or in the ED, or you're moving this patient from a floor bed to your  ICU, of course, ABCs, doing a focused neurological assessment, checking the pupils, seeing what the patient's level of consciousness is, are they able to respond to commands or not.  And when you give them painful stimulus, if they're not responding to voice or not really following commands, looking for any asymmetry, that's also going to help you determine what  kind of imaging studies you want to get as soon as you have your ABC secured, and your first and second-line agents have already been administered.  And after you've secured someone's AB, what is your choice of sedation going to be? And at what dose do you want to start administering these?  And in terms of the additional imaging studies, whether you're going to choose CT, MRI, are you going to get vessel imaging or not, that will be guided by the clinical scenario.  My recommendation would be if it's a vascular pack, it is worthwhile getting vessel imaging the first time you stick the patient in the scanner, and imaging both the arterial phase  as well as the venous phase, depending upon the clinical scenario, will give you a lot of information that will help guide your treating the seizure symptomatically, but  it will help guide and give you an idea about the potential underlying cause and whether the cause is going to be reversible or not.  As an example, a patient could very well be having a large vessel occlusion from cardioembolic  stroke and seize at the time of onset of their strokes and could very well slip into status epilepticus, but they also need emergent treatment for their large vessel occlusion.  So it's going to help you parallel process and help you both treat the status epilepticus as well as treat the large vessel occlusion by activating your angio suite, your stroke  team at the same time. This is a nice algorithm from the American Epilepsy Society's guideline statement.  This essentially breaks it down again by the different therapy times that we just discussed. A few considerations for the ICU.  Some of these patients are going to require replacement therapy, or they may have preexisting  and staged renal disease, or they may develop distributive shock as you're ramping up some of the third line medications.  Some of the AEDs, some of our anti-epileptic drugs are greenly cleared. You've got to remember to dose or re-dose after dialysis.  For example, for Keppra, in an end-stage renal disease patient who's on hemodialysis, you may choose to treat them with 500 milligrams of Keppra.  Make sure you give them 500 milligrams of Keppra or Lepturacetam after their dialysis treatment as well.  And medications such as Dilantin that are very heavily protein bound will not be dialyzed. For plasmapheresis, some of these patients are going to, patients particularly who come  in with autoimmune encephalitis or paraneoplastic encephalitis are going to also require plasmapheresis.  And as you're trying to treat their status epilepticus and taking care of the underlying etiology for their status, some of these medications may get removed during plasmapheresis.  So one potential way of avoiding that is avoid administering the drugs right before you're going to plasmapherese somebody.  Monitoring just one quick word about monitoring drug levels. So there are some of these medications have narrow therapeutic windows such as Dilantin.  So making sure that you get levels both after loading a patient. Another good rule to remember is two hours after loading a patient with Dilantin, valproic  acid, phenobarbital, get a level. And then you can check daily levels till you reach a steady state.  And specifically making sure that you're looking for drug-drug interactions will also help in preventing adverse events.  I just wanted to, although I'm not going to talk about some of these therapies that have been described for status epilepticus patients such as hypothermia or inhaled anesthetic  medications or electroconvulsive therapy, ketogenic diet, I will not have the time to go into some of those therapies.  I just wanted to point out that the Norse Institute, this entity of new onset refractory status epilepticus, our critical care community should be aware of this entity.  Specifically, this will be seen in patients who were previously completely healthy. Most of these patients tend to be young and they develop super refractory status epilepticus.  And there's a very nice checklist that this group that's been working on both defining Norse as well as identifying what the different etiologies of Norse could be.  And also proposing an algorithm for how to treat these patients.  This is a nice resource. And here's another snapshot, just putting everything together as a treatment algorithm. This is from Yale, also available on the Norse Institute website.  And our treatment algorithm at Mount Sinai looks very similar to what's been proposed here. So before we wrap up, just a quick word on the third-line agents, doses, propofol,  midazolam, ketamine, phenobarb.  You're going to bolus these and you're going to start the drip. Of course, all of these are going to cause hemodynamic instability, making sure that  you have pressers readily available at the bedside as you're beginning to uptitrate as well as bolus some of these medications.  Most of these you're going to, if you have your patient hooked up to continuous EEG monitoring, make sure you're standing at the bedside, speaking to your epileptologist, getting a  read every two to five minutes so that you can ramp up, re-bolus, increase the drip by the same amount that you bolus the patient with.  For example, if you're going to use 0.2 milligrams per kg of midazolam, you're going to bolus  0.2 milligrams per kg, start the drip at 0.2 milligrams per kg per hour, look at the EEG,  get a read or look at your patient clinically, and if your patient is still seizing, increase the drip by 0.2 milligrams per kg per hour after re-bolusing 0.2 milligrams per kg till  the seizures terminate or till the electrographic seizures terminate, and you're going to aim for, should you aim for seizure suppression versus birth suppression?  Again, it's controversial, but in my practice, I tend to aim for seizure suppression. It allows us to aim for, to treat our patients with lower, potentially lower doses of some  of these third-line agents, but sometimes, depending upon the underlying etiology as well as how long it's taken to suppress someone's seizure, you may, seizures you may need to  target birth suppression as well. And typically, we leave patients on these third-line agents for 24 to 48 hours from  their last seizure and begin to wean these, wean the third-line agents down only after optimizing the second-line agents.  So just bringing everything together, the principles of management will remain the same as any, any other neuroemergency, ABCs will always come first, symptomatic treatment of  the seizures, identify the underlying primary cause and prevent secondary neurological injury and prepare your patient for success.  So I'd like to acknowledge our patients and families, our neurocritical care team at the Icahn School of Medicine at Mount Sinai.  And specifically, I'd like to thank Nicole Davis, our neurocritical care pharmacist for help with some of these slides. Thank you very much.

Video Summary

Dr. Neeta Gayage, a neurointensivist from the Icahn School of Medicine at Mount Sinai, discusses the latest clinical consensus and guidelines for managing seizures and status epilepticus in the ICU. Seizures are transient occurrences of abnormal neuronal activity and account for about 1 million ED visits each year. Status epilepticus is defined as seizures lasting five minutes or longer, recurrent seizures without return to baseline, or continuous clinical or electrographic activity. It is important to recognize and treat seizures early to prevent the development of status epilepticus. Initial therapy includes administering appropriate doses of antiepileptic drugs (AEDs) such as lorazepam, midazolam, or valproic acid. Second-line agents can be considered if seizures persist, and third-line agents may be needed for refractory cases. The choice of sedation and monitoring drug levels is also important. Dr. Gayage also mentions the new onset refractory status epilepticus (NORSE) and highlights a treatment algorithm for refractory status epilepticus.

Asset Subtitle

Neuroscience, 2021

Asset Caption

The Society of Critical Care Medicine's Critical Care Congress features internationally renowned faculty and content sessions highlighting the most up-to-date, evidence-based developments in critical care medicine. This is a presentation from the 2021 Critical Care Congress held virtually from January 31-February 12, 2021.

Learning Objectives

Apply the latest clinical consensus and literature regarding evaluation and management of seizures and status epilepticus in the ICU
Evaluate patients in the ICU who have altered mental status and differentiate among acute neurologic emergencies
Determine better clinical decisions for managing patients with intracranial hemorrhage and decisions regarding anticoagulation or reversal in patients with brain bleeds

Seizures and Status Epilepticus: The Shakes and Bakes in the ICU
Neha S. Dangayach

Meta Tag

Content Type Presentation

Knowledge Area Neuroscience

Knowledge Level Intermediate

Knowledge Level Advanced

Membership Level Select

Tag Seizure

Year 2021

Keywords

neurointensivist

seizures

status epilepticus

ICU

antiepileptic drugs

NORSE

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