Careful review of medication list, focusing on any recent changes (look up drugs individually to determine if they lower seizure threshold, or if they participate in drug-drug interactions with other medications that affect seizure threshold).
? Preceding febrile illness or other complaints.
? Use of alcohol or other substances.
? Seizure initiated with focal symptoms, with subsequent generalization (this suggests focal neurologic
pathology).
neuro exam
Immediately following the seizure, patients may have focal neurologic defects in areas involved in the seizure (e.g., Todd's paralysis, focal hyperreflexia, or aphasia).(34697528)
💡 Prompt examination is important, as findings may disappear over time.
A transient, focal neurologic deficit is
important for two reasons:
(1) This supports that the event as truly a seizure.
(2) Focality suggests a focal neurologic lesion as the trigger of the seizure. This increases the importance of neuroimaging.
labs to consider:
🚨 Fingerstick glucose (should be done immediately).
Chemistries, including Ca/Mg/Phos.
Complete blood count.
Coagulation
studies (INR, PTT).
Liver function tests, including ammonia level.
Creatinine kinase (to evaluate for rhabdomyolysis due to seizures).
Pregnancy test if relevant (serum/urine human chorionic gonadotropin level).
Albumin (may help interpret phenytoin level).
Urinalysis.
Toxicology workup as indicated (e.g. urine toxicology screen including cocaine and methamphetamine).
📖
Antiseizure medication levels:
Valproic acid, phenobarbital, and phenytoin levels are often available locally, with a reasonably rapid turnaround time.
Other antiseizure medication levels are typically send out tests (e..g., levetiracetam, carbamazepine, lacosamide). These may remain useful later on, to establish compliance.
Remember that primidone is metabolized
into phenobarbital. If a patient is on primidone, check a phenobarbital level.
💡 Antiseizure medication levels don't affect immediate management, but these may be helpful later on in determining the best long-term maintenance antiseizure medication regimen.
CT scan
CT head generally indicated unless cause is obvious (e.g., non-adherence with antiseizure medications).
CT perfusion may reveal focal areas of
cortical hyperperfusion. More on CT perfusion scans here: 📖
MRI
(1) The main reason to obtain an MRI is to evaluate for underlying pathology.
(2) MRI may reveal evidence of seizures themselves. This may occasionally be helpful in the diagnosis of NCSE (nonconvulsive status epilepticus). MRI abnormalities may take several weeks to resolve, so these don't
necessarily represent active seizure activity.
(a) Hyperintensity on DWI (diffusion-weighted imaging) is the most commonly seen abnormality, which can be accompanied by T2 hyperintensity. This can reflect either vasogenic or cytotoxic edema (with the later reflected by a reduction in the ADC (apparent diffusion coefficient)).(34034086) Restricted diffusion may occur in the
cortical ribbon, hippocampus, or thalamus (especially the pulvinar). The contralateral cerebellum may also be involved. One series found thalamic diffusion restriction in half of patients with focal-onset status epilepticus.(35393970) Diffusion changes which don't correspond with a vascular distribution support the diagnosis of status epilepticus, rather than
an acute ischemic stroke.(34034086)
(b) Leptomeningeal contrast enhancement may sometimes be seen.(34034086)
lumbar puncture
The main indication is usually exclusion of meningitis or encephalitis, if this is suspected clinically. Potential
indications for lumbar puncture include the following:(Wijdicks, 2019)
Fever.
Infectious symptoms prior to seizure.
Neuropsychiatric symptoms suggestive of anti-NMDA receptor encephalitis.
Known immunosuppression.
No apparent cause for the patient's status epilepticus.
MRI reveals leptomeningeal enhancement.
Note that prolonged status epilepticus itself can cause elevation of protein and total cell count (but
not above ~80-100/mm3).
New onset seizure is an indication to obtain head imaging with CT prior to proceeding with lumbar puncture. Check a CT to rule out mass effect in all new-onset seizure patients.
If a lumbar puncture is performed, consider obtaining an autoimmune encephalitis panel.
management
EEG
EEG is usually indicated (unless the patient's mental status returns to normal).
Re-examine
the patient and review the EEG to confirm that seizures have been controlled.
antiseizure medication(s)
Confirm that the patient has been loaded adequately (proper dose ordered & given).
Consider checking a post-load antiseizure medication level in some cases (for fosphenytoin 📖 or valproic acid
📖).
Ensure that orders for future antiseizure medications are correct (appropriate doses and administration times).
If a sedative infusion is being used to control seizures (e.g., propofol), make sure that this isn't stopped prematurely for a daily sedation interruption.
Review for any drug-drug interactions.
vitamins
IV thiamine if deficiency is possible.
📖
IV/PO pyridoxine if deficiency is suspected. 📖
rhabdomyolysis management
Review creatinine kinase & risk for rhabdomyolysis.
Manage if present. 📖
nutritional support
For
intubated patients, early initiation of enteral nutrition may reduce the risk of propofol infusion syndrome.
causes
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Many factors often combine to lower the patient's seizure threshold, leading to status epilepticus. Ideally, all factors should be addressed, reducing the likelihood of recurrence.
In some cases,
it may be possible to separate seizures into those with partial onset versus those with generalized onset. Metabolic disorders and diffuse brain injury will usually have a generalized onset, whereas a discrete lesion in the brain tends to lead to partial-onset seizures.
metabolic
Hyponatremia/hypernatremia.
Hypoglycemia/hyperglycemia (hyperglycemia may tend to cause focal seizures).
Hypophosphatemia.
Hypomagnesemia.
Hypocalcemia.
Hypoxemia, anoxic brain injury.
Respiratory alkalosis.
Uremia, dialysis disequilibrium.
Hyperammonemia (of any cause); hepatic encephalopathy.
Hyperthermia.
Hypothyroidism.
Deficiency of thiamine (Wernicke encephalopathy), B12, or pyridoxine.
malignancy
Parenchymal brain tumor (either primary or metastatic).
Leptomeningeal metastases.
Complication of radiation
therapy (e.g., radiation necrosis).
Complication of chemotherapy (agents listed below).
Withdrawal of benzodiazepines, barbiturates, baclofen, gabapentin, or antiseizure medications.
(3) Toxicologic:
Alcohol withdrawal.
Carbon monoxide poisoning.
Overdose with sympathomimetic, salicylate, tricyclic,
anticholinergic, lithium, or synthetic cannabinoids.
definition of status epilepticus
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definition of status epilepticus
The definition of status epilepticus has evolved considerably over the past two decades, leading to some inconsistencies. Nonetheless, any of the following may reasonably
be considered status epilepticus:(33896531)
(1) Generalized tonic-clonic seizure that either lasts >5 minutes, or occurs multiple times without regaining normal mental status inbetween.
Generalized tonic-clonic seizures should cause diffuse motor activity and loss of consciousness.
Self-terminating seizures will generally stop within <5 minutes, so persistence beyond 5 minutes
implies that active medical therapy is required to stop the seizure.
(2) Focal seizure with impaired awareness that lasts >10 minutes. This must be differentiated from a simple aware seizure (e.g., movement of one extremity with retention of consciousness).
classifications of generalized convulsive status epilepticus
Refractory Status Epilepticus (RSE): Refractory to first- and
second-line antiseizure medications (e.g., benzodiazepine plus levetiracetam). This occurs in about a quarter of patients presenting with status epilepticus.(34798964)
New-onset Refractory Status Epilepticus (NORSE): refractory status epilepticus occuring in the context of new-onset status epilepticus in a patient with no history of
seizure.📖
Febrile infection-related epilepsy syndrome (FIRES): subcategorization of NORSE wherein of status epilepticus occurs 1-14 days after a febrile illness.📖
Super-Refractory Status Epilepticus (SRSE): Refractory to two antiseizure medications and general anesthesia treatment for 24 hours, or when
seizures reemerge during an attempted anesthetic wean.(33896531)
This is more likely to be due to acute encephalitis.(30516601)
Prolonged super-refractory status epilepticus (PSRSE): Super-refractory status epilepticus which lasts for >7 days, including ongoing need for
anesthetics.(33896531) An example of this may be epilepsia partialis continua.
epilepsia partialis continua
This involves ongoing simple, focal seizures (e.g. twitching of a single extremity without alteration of consciousness).
This is generally not life-threatening, as it doesn't affect consciousness or airway protection.
It can persist for months or years.
Treatment is extremely challenging, with seizures often being refractory to multiple medications. Some restraint may be needed, as the treatment may be more dangerous than the disease itself.
seizure mimics
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“Convulsive syncope” (Cardiogenic syncope may cause brief convulsive movements including
myoclonus, head/eye deviation, or automatisms).
Propofol frenzy. 📖
Rigors.
Spontaneous sustained clonus.
Tremors.
Myoclonus. 📖
Dystonia. 📖
Paroxysmal sympathetic hyperactivity
(PSH). 📖
Migraine aura.
Transient ischemic attack (TIA, including limb-shaking TIA).
pseudoseizure
(technical terminology varies including “Paroxysmal Non-Epileptic Seizures” or “psychogenic, non-epileptic attacks”)
Clinical phenomenon which mimics a seizure, often related to psychiatric stress.
Patients are not aware that this isn't a real seizure (they aren't “faking it”).
Can occur in patients with epilepsy, creating a very confusing picture (patients can have episodes of both genuine seizures and pseudoseizures).
⚠️ ~15% of
patients admitted to ICU for status epilepticus may actually have pseudoseizure.
clinical clues suggesting pseudoseizure
(1) Retained consciousness:
Movement of all extremities with preservation of consciousness (e.g. speaking or following commands).
Responsiveness to noxious stimuli (e.g., nasal swab for influenza).
(2) Unusual movements:
Out-of-phase movement of limbs (in true generalized seizure, the
limbs generally move synchronously).
Pelvic thrusting or overarching of trunk (opisthotonic posturing).(35393970)
Side-to-side head movement.
Very irregular movements.
Changing side and region of body abruptly, without a “marchlike” propagation.(35393970)
(3) Ocular
findings:
Eyes that are squeezed shut (true generalized status epilepticus patients should be unconscious and not resist eyelid raising).
Irregular eye movements (unliked consistent gaze deviation that may be seen in seizure).
Optokinetic nystagmus: viewing an optokinetic drum or video will elicit nystagmus.🎥
(4) Lack of a postictal period.
clinical
clues suggesting epileptic seizure
Emesis.
Lateral tongue laceration.
Elevated lactate level.
Elevated creatinine kinase level.
⚠️ Urinary incontinence may occur with either seizure or pseudoseizure.
evaluation and management
When in doubt, video EEG capture can help make these distinctions.
If a diagnosis can't be made with certainty, the safest approach can be to treat these
as genuine seizures (e.g. with benzodiazepine, airway protection).
initial treatment
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This algorithm describes the approach to a convulsive generalized seizure lasting >5 minutes. For a patient with recurrent seizures who isn't actively seizing, a more gradual approach may be taken (with
escalation if an active seizure re-emerges).
The duration of time in which a patient can be in convulsive status epilepticus before brain damage occurs is unknown. Many experts estimate this to be around 30 minutes.(30516601) Consequently, the above algorithm is designed to break nearly all seizures within 30 minutes. This requires rapid escalation to intubation.
The following
sections explore parts of this algorithm in more detail:
Benzodiazepine
Hypoglycemia, hyponatremia, and thiamine deficiency
Conventional antiseizure medication
Neurolytic intubation
benzodiazepine is front-line therapy
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when to give benzodiazepine
Most seizures are self-limited. Often this will involve a tonic phase, followed by a clonic phase, and finally a post-ictal
phase. If the patient is still in a tonic phase after three minutes, it is unlikely that their seizure will break spontaneously.
After five minutes of seizure, start aggressive benzodiazepine administration.(22335736)
dosing
IV lorazepam is generally the preferred agent.
The best research supports a dose of
0.1 mg/kg lorazepam IV.(9738086, 33664203)
However, many guidelines recommend giving 4 mg IV initially, with a repeat dose if this isn't effective. That may also be reasonable.
For patients without IV access, give 10 mg intramuscular
midazolam.(21967361)
Diazepam:
10 mg IV, may repeat q5-10 minutes to a maximum cumulative dose of 30 mg.
Rapid redistribution of diazepam from the brain into the peripheral tissues limits its duration of action, which may increase the risk of recurrent seizures as the diazepam wears off.
do not under-dose your benzodiazepine
The
reason is that over time, GABA receptors on neurons are internalized within cells. This reduces the sensitivity of neurons to benzodiazepines.
Up-front adequate dosing of benzodiazepine provides the best chance for immediate lysis of the seizure.
Evidence does NOT support the concept that benzodiazepines for status epilepticus promote respiratory depression and intubation. In fact, adequate doses of benzodiazepines may reduce the need for
intubation. One caveat here is that the clinician must be patient in allowing the postictal, post-benzodiazepine patient to wake up (these patients will have altered mental status, but by itself that's not an indication for intubation).
don't stop here!
Even if the benzodiazepine breaks the seizure, you still need to give the patient a conventional antiseizure medication (e.g., levetiracetam).
hypoglycemia,
hyponatremia, and thiamine deficiency
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exclude hypoglycemia
Hypoglycemia must be excluded in any patient with seizures or mental status changes.
Usually a finger stick-glucose is adequate for this. However, if there is difficulty obtaining a finger-stick glucose or if the measurement is borderline, just give IV glucose
empirically (1-2 ampules of D50W).
treat hyponatremia if present
Hyponatremia is an uncommon cause of seizures. However, this is important because seizures due to hyponatremia should be treated with hypertonic saline immediately.
Standard therapy would be a bolus of 150 ml 3% saline, which may be repeated once for ongoing seizure.
Hypertonic saline often takes 15-20 minutes to arrive from pharmacy. In
an emergency, 2 amps of bicarbonate (each amp equals 50 mEq bicarbonate in 50 ml) can be substituted for 150 ml of 3% saline.🌊
thiamine deficiency
Thiamine (B1) deficiency is known to cause seizures.
This is most common in children, but can occur in adults as well (especially in the context of alcoholism).
Treat
with empiric IV thiamine.
conventional antiseizure medication
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conventional antiseizure medication is indicated for ALL status epilepticus patients
Any patient who seizes for >5 minutes should receive an antiseizure medication, even if benzodiazepine is successful in stopping the seizure. The benzodiazepine
will last only for a few hours, so treatment with benzodiazepine alone leaves the patient at risk for delayed seizure recurrence.
There is no reason to intentionally delay the conventional antiseizure medication until after the benzodiazepine (because it will be required regardless).
For a patient with active convulsive seizures, don't delay intubation while waiting for the antiseizure medication to arrive from the pharmacy.
The antiseizure medication should be ordered
ASAP and given as early as possible.
If the anti-epileptic arrives from pharmacy and breaks the seizure within 20 minutes then intubation isn't necessary. That would be terrific, but in most scenarios this is logistically impossible.
Intubation shouldn't be delayed while waiting to see if the second-line antiseizure medication agent will work (target intubation by ~20 minutes after seizure initiation, regardless of whether or not the conventional antiseizure medication has
arrived).
loading dose for patients on chronic antiseizure medication therapy
All patients with status epilepticus should be loaded with an antiseizure medication (usually levetiracetam, fosphenytoin, or valproate).
For patients on one of these drugs previously:
If the patient is believed to be adherent with therapy, it could make sense to load with a different drug. For example, a valproate load could be used in
a patient on chronic levetiracetam.
If the patient is felt to be potentially non-adherent, then re-loading with the patient's chronic anti-epileptic could make sense.
When in doubt, levetiracetam may be a good choice here (because supra-therapeutic levels are reasonably safe).
neurolytic intubation
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preparation for
intubation
Propofol is generally the best induction drug here, given its potent anti-epileptic activity. The only exception would be a patient with severe hypotension (in whom midazolam provides more hemodynamic stability). Ketamine has anti-epileptic activity as well, which may function synergistically with propofol or midazolam (ketamine blocks NMDA receptors, while propofol blocks GABA receptors).
The combination of sedation, vasodilation from
propofol, and positive pressure ventilation may decrease the blood pressure. Be prepared for this (e.g. have a norepinephrine infusion and/or push-dose epinephrine ready).
Regarding paralytic:
Succinylcholine may be contraindicated in prolonged status epilepticus, as this may lead to rhabdomyolysis and hyperkalemia.
Rocuronium causes prolonged paralysis, which may be problematic because it can mask ongoing seizure activity. However, sugammadex can be
used following intubation to reverse paralysis and determine if there is residual seizure activity (if EEG isn't readily available).
Note that muscular paralysis won't prevent brain damage from ongoing seizure activity. The goal is always to control the seizure itself, not to mask it using paralytics.
Placement of a tourniquet on an extremity before paralysis may prevent paralytic from entering that extremity, thereby allowing you to determine if the seizure has
been terminated.
example of a neurolytic intubation
There are many ways to accomplish this. One strategy involves the following sequence of drugs:
#1: Push 200 mg IV ketamine.
#2: Push 100 mg of propofol (10 ml).
#3: Push 0.6 mg/kg rocuronium (this is a lower dose than is usually used, so that it will take a bit longer to work than usual and won't last too long).
This will result in one of two outcomes:
(#1) The ketamine and propofol will usually break the seizure. This results in an abrupt cessation of motor activity about 30-60 seconds after pushing the propofol (before the onset of paralysis). You can usually intubate the patient when that occurs – the patient is generally quite flaccid.
(#2) The ketamine and propofol fail to break the seizure. In this case, seizure movements will
gradually become less pronounced as paralysis occurs. Disappearance of all movement generally occurs >60 seconds after administration of rocuronium.
Based on the dose and sequence of drugs used, the rocuronium isn't generally really needed here (the propfol and ketamine will generally break the seizure and produce adequate intubating conditions). The rocuronium is merely an insurance policy so that in case the propofol and ketamine don't
break the seizure, you will still get adequate intubating conditions.
initiate sedative infusion (propofol)
Propofol (+/- ketamine) will generally break the seizure. However, an ongoing infusion of propofol is still needed to prevent seizure recurrence.
If possible, propofol should be infused at a moderate-high rate (e.g. 50-80 mcg/kg/min). A low dose of vasopressor may be needed to allow for propofol administration.
Phenylephrine may be preferable here for patients without central access.
For severely hypotensive patients, a midazolam infusion may be used instead of propofol. The main drawback of midazolam is that it accumulates and wears off slowly, delaying extubation.
refractory status epilepticus
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Rarely, seizures may fail to respond to benzodiazepine, antiseizure medication therapy, and anesthesia. This is a largely
evidence-free zone. The algorithm above shows one reasonable approach.
overall strategy towards refractory status epilepticus
Both antiseizure medications (e.g., levetiracetam, valproic acid, lacosamide) and continuously infused anesthetic agents (e.g., propofol, ketamine) should be simultaneously escalated until seizure control is achieved.
A common mistake is to focus excessively on one component of therapy (usually titration of the anesthetic
agent) while forgetting to escalate antiseizure medications.
Make sure to maximize the dose of each antiseizure medication. For status epilepticus it's generally preferable to start with high doses to achieve seizure control (followed by gradual tapering over time).
Pentobarbital coma is the treatment of last resort. Pentobarbital coma is highly effective, but also fairly morbid. Due to the long half-life of
pentobarbital, a high-dose pentobarbital coma obligates patients to spend a long time on mechanical ventilation. Pentobarbital also causes substantial hypotension and ileus.
Once seizure control is achieved, therapies are typically continued for about one day.(34300194) Subsequently, the anesthetic agent may be gradually weaned off. The optimal rate of weaning off anesthetic infusions
is not known. Ideally, this will result in the patient awakening without recurrent seizure. It is essential to continue maintenance antiseizure medications throughout this period and beyond.
selection of antiseizure medication
Front line: Levetiracetam 📖
Levetiracetam is increasingly being utilized as a front-line
antiseizure medication.
Levetiracetam is equally effective compared to other agents (e.g., fosphenytoin or valproic acid), yet it has a superior safety profile and is very easy to use.
Levetiracetam has no contraindications, so this is a convenient agent to order for patients who present in status epilepticus (without any additional information known about the patient).
Second line: Valproic acid
📖 or fosphenytoin 📖
These more traditional agents remain good options for most patients.
Valproic acid and fosphenytoin interact with one another, so only one of these can be utilized.
Both agents have similar efficacy, so the choice may depend on patient comorbidities or contraindications.
In
general, valproic acid may be a bit safer, easier to use, and more effective (since valproate levels are easier to interpret and valproate is subject to fewer drug-drug interactions).(33664203, 33480193)
Third line: Lacosamide
📖
Lacosamide is a newer agent which is generally safe and easy to use, with few drug-drug interactions.
The efficacy of lacosamide is less well established than valproic acid or fosphenytoin, pushing it to third place here. However, for multimorbid patients who have contraindications to valproic acid and fosphenytoin, lacosamide could be a rational second-line agent.
Fourth line:
Phenobarbital 📖
Phenobarbital is an effective antiseizure medication, but it is difficult to titrate and may lead to somnolence. Thus, for most patients phenobarbital isn't a front-line agent. However, for patients with alcohol withdrawal seizure, phenobarbital is the preferred antiseizure therapy.
(Don't confuse phenobarbital with high-dose pentobarbital
coma 📖. Although these are similar agents, pentobarbital coma involves giving a much, much higher dose.)
selection of continuously infused anesthetic agents
First line: Propofol 📖 or midazolam
📖
Either of these agents has traditionally been utilized as a front-line anesthetic.(34300194)
Propofol has the advantage that it is more easily titratable. For many patients, utilizing propofol may allow for rapid seizure lysis followed by extubation within <24 hours. Alternatively, high-dose midazolam
infusions often take a long time to wear off so they may delay extubation.
Second line: Ketamine 📖
Ketamine inhibits NMDA receptors, so it may function synergistically with either propofol or midazolam (which work via the GABA receptor).
Ketamine is highly effective, with a considerably superior side-effect profile compared to pentobarbital coma.
Third line: Pentobarbitalcoma 📖
NORSE
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definition
New-onset Refractory Status Epilepticus (NORSE): Refractory status epilepticus occuring in the context of new-onset
status epilepticus in a patient with no history of seizure and no clear cause of seizure.
Febrile infection-related epilepsy syndrome (FIRES): Subcategorization of NORSE wherein of status epilepticus occurs 1-14 days after a febrile illness.
Early empiric therapy with high-dose steroid, plasma exchange, and/or IV immunoglobulin may be considered.(33896531)
neuromonitoring
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clinical monitoring
If patients can regain normal consciousness, they aren't
seizing.
An inability to regain consciousness raises concern for persistent non-convulsive status epilepticus (NCSE).
video EEG (vEEG)
Continuous vEEG is preferred (especially for more complex patients). For patients who don't regain normal consciousness, intermittent seizures may be occurring which could be missed with a single “spot” EEG.
There is no consensus or data regarding whether it is best to titrate medication to target
burst-suppression or simply the absence of seizures.
Targeting a deeper level of sedation (e.g. burst-suppression) will generally increase time on ventilation and medication-related complications.
In the absence of clear evidence, simply targeting the absence of seizures may minimize iatrogenic harm.(33664203)
vEEG can lead to over-treatment and iatrogenic harm, if:
(1) A decision is made to target burst-suppression or flat-line EEG for prolonged periods of time.
(2) Efforts are made to suppress all ictal-spectrum patterns (e.g. lateralized periodic discharges). When weaning from anesthetic coma, the emergence of ictal-interictal continuum activity may be transient and doesn't necessarily require treatment intensification.(34618762)
waking & weaning
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basic considerations prior to extubation
(1) Have all causes of the seizure been addressed?
(2) Are any further diagnostic tests needed?
MRI is easier and safer to do when intubated; after intubation patients will often not be able to lie still enough for MRI.
LP is easier to
perform prior to extubation.
(3) Have adequate doses of anti-epileptic medications been given?
extubation
Once the above criteria have been met, sedation can be lifted.
Most patients will be kept intubated at least one day. For very refractory seizures, a longer period of sedation may be needed.
Careful monitoring is required to determine if there are any ongoing seizures. Subsequently, the patients may be
extubated if they meet other criteria (e.g., spontaneous breathing trial).
supportive medical management
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Rhabdomyolysis is common among patients with prolonged status epilepticus. The diagnosis and management of rhabdomyolysis is explored here 📖.
Neurogenic
pulmonary edema may occur. 📖 (34619776)
Myocardial infarction or takotsubo cardiomyopathy 📖 may occur due to physiological stress.(34619776)
Propofol
infusion syndrome is often a concern. Close monitoring of triglyceride levels is appropriate.
antiseizure medications
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rough classification of medications
Main antiseizure medications:
Levetiracetam
Valproic acid
Fosphenytoin
Lacosamide
Phenobarbital
Anesthetic infusions:
Propofol
Ketamine
Midazolam infusion
Pentobarbital coma
Other:
Topiramate
Thiamine
Pyridoxine
Ketogenic diet
Antiseizure medication teratogenicity
general comments
Antiseizure medications often have similar efficacy when compared to one another in clinical trials (e.g., the ESETT trial).(31774955) Consequently, the optimal agent(s) are controversial and
subject to substantial variation between institutions. It may be reasonable to select agents predominantly based upon which are safe and easy to use.
During an episode of ongoing status epilepticus, there is a reduction in the number of inhibitory GABA receptors and an increase in the number of stimulatory glutamate receptors (e.g. NMDA receptors). Thus, the efficacy of agents targeting GABA receptors may decrease over time, whereas the efficacy of agents
targeting glutamate receptors may be preserved over time.(34221552) This provides a rationale for the use of ketamine in super-refractory status epilepticus (since it functions as an NMDA receptor).
There is little clinical evidence to support any specific combination of antiseizure medications as synergistic. However, it seems logical to combine agents with different mechanisms of action,
when possible.(33176370) Alternatively, the combination of two sodium-channel blockers may cause increased adverse effects (e.g., phenytoin plus lacosamide).(30921021) A reasonable combination of agents to use among critically ill patients may often be levetiracetam, +/- lacosamide, +/- valproic
acid. One reasonable sequence of agents is shown below.
therapeutic drug monitoring
Monitoring of drug levels generally available for phenytoin 📖, valproic acid
📖, and phenobarbital 📖.
Trough levels are generally most useful, as these reflect the minimal drug concentration achieved (corresponding to the highest risk of breakthrough seizure).(33176370, Torbey 2019)
Valproic acid and phenytoin
bind albumin, so measurement of a free drug level is more accurate than the total drug level. However, most hospital laboratories lack the ability to rapidly measure free drug levels, so these are not measured routinely.
In super-refractory status epilepticus, it may be desirable to target drug levels at the higher end of therapeutic ranges.(34619776)
levetiracetam
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dosing 💊
Load: 60 mg/kg up to a max of 4.5 grams, infused over 10 min. (Any patient >69 kg should receive 4.5 grams.)
If still seizing, may give an additional 20 mg/kg IV (max
1500 mg) over 5 minutes.(33896531)
Maintenance:
Usually 1 – 1.5 grams q12hr (with a range of 1,500-4,500 mg/day divided q6hr-q12hr).(33896531)
Recently there has been a trend towards using higher maintenance doses, with 1.5 grams q12 being
used initially for most patients in status epilepticus.(34798964) After patients have stabilized, the dose may be stepped down to optimize long-term tolerance.
Levetiracetam is renally cleared:
In renal insufficiency, the maintenance dose may need to be reduced. (The loading dose is the same regardless of renal
function.)
For patients with augmented renal clearance (ARC) 📖, there is a risk of obtaining subtherapeutic levetiracetam levels.(35449037)
contraindications
None, although levetiracetam may be suboptimal in profound renal failure.(34221552)
side effects
Mood disturbance, agitation, psychosis. Pyridoxine could possibly have a role in management of behavioral side-effects (possibly at a dose of 100 mg PO TID).(Albin 2022; 33823377)
SIADH (syndrome of inappropriate antidiuretic hormone secretion).
Sedation/somnolence, especially in elderly patients.(33480193; 34619776)
indications & advantages
Levetiracetam is rapidly becoming the front-line agent for management of
status epilepticus.
A recent randomized, blinded trial demonstrated that levetiracetam, fosphenytoin, and valproate have equivalent efficacy in the management of status epilepticus.(31774955)
Benefits of levetiracetam include:
It has essentially no contraindications – so you can safely prescribe this to patients without knowing much about them.
It can be infused
rapidly.
It is extremely safe; in particular, it is unlikely to cause alteration in consciousness. (31766004)
It has minimal interactions with other drugs.
pharmacology, mechanism of action
Bioavailability is extremely high, allowing a 1:1 conversion between PO and IV dosing.
Renally cleared, so dose should be reduced in renal failure.
Alternatively, elimination may be enhanced in patients with augmented renal clearance (ARC) 📖 – who may need higher doses than usual.(33176370)
The half-life is ~6-8 hours.(30921021)
Mechanism of action is
unclear (may bind to synaptic vesicle protein SV2A causing a nonspecific decrease in neurotransmitter release).(34300194; 30921021)
valproic acid
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dosing
💊
(#1) Loading dose: 40 mg/kg up to 3,000 mg, over 5-10 min.(34300194))
If still seizing may add 20 mg/kg up to 2,000 mg over 5 min.
(#2) May check a serum level 1 hours after the load.(Albin 2022)
Practice varies between centers regarding to how often this is measured. A level should especially be considered for patients with unusual pharmacokinetics (e.g., morbid obesity).
(#3) Maintenance: 15-60 mg/kg total daily dose which is divided TID (e.g., ~10 mg/kg q8hr, or ~500-750 mg IV q8hr).(34798964)
Dosing in renal impairment:
No adjustment necessary, but free valproic levels may be elevated due to reduced binding to albumin.
Dosing in hepatic impairment: Contraindicated in severe impairment.
contraindications
Pregnancy.
Hyperammonemia:
Severe liver disease.
Urea cycle disorder.
Mitochondrial disorder.
Thrombocytopenia (valproic acid may cause mild thrombocytopenia in ~1/3 of patients)
Drug interactions:
Avoid combining valproic acid with fosphenytoin 📖, carbapenems, or topiramate.
Valproic acid may increase free
levels of warfarin, so monitor the INR closely.
side effects
Hyperammonemia, encephalopathy, sedation.
Stevens-Johnson syndrome (rare).
Drug reaction with eosinophilia and systemic symptoms (DRESS).
Nausea,
vomiting, and anorexia.(30921021) Enteral liquid valproic acid may be more likely to cause gastrointestinal distress.(34697528)
Parkinsonism.
Known teratogen; contraindicated in patients who may be pregnant.
indications & advantages
Valproic acid is
a good option, which is effective and generally well tolerated. It has a broad spectrum of activity against a variety of seizure types.
Valproate is also used for its mood stabilization properties. Thus, valproic acid could be a good choice for patients with agitated delirium or known psychiatric disorders. More on the use of valproic acid as a sedative here.
A limitation
with valproic acid is that interferes with the pharmacokinetics of phenytoin 📖 or phenobarbital. If the patient doesn't respond to valproic acid, this may render it challenging to add additional antiseizure medications. Valproate also inhibits the metabolism of lamotrigine.(33896531)
pharmacology,
mechanism of action
Mechanism of action: Prolonged recovery phase of voltage-gated sodium channels, enhanced GABA signaling.(34300194)
Valproate has a bioavailability of >90%, so it may be given either enterally or intravenously (with a 1:1 conversion). However, the extended-release formulation of valproic acid is less bioavailable by
~15%.(34697528; Albin 2022)
At moderate blood levels (e.g., <75 mg/L or <525 uM/L), valproate is almost entirely bound to albumin (with a relatively low free valproate level). With increasing valproate levels, an increasing fraction of the drug is present in its free form – so the biologically effective level of valproate will increase markedly.
Circulating fatty acids displace valproate from protein binding, potentially increasing the concentration of free valproate. (Louis 2021)
Levels of free valproic acid may be increased in the following situations:(28833346)
Hypoalbuminemia.
Uremia.
Medications which displace valproate from albumin (e.g., aspirin, ibuprofen, propofol, clevidipine, phenytoin, and
intravenous fat emulsion).
Concern for signs/symptoms of valproate toxicity.
Valproate undergoes hepatic metabolism with a half-life of ~9-19 hours. It is primarily metabolized via glucuronidation and mitochondrial beta-oxidation, usually with a minor contribution from CYP 2C9 and 2C19. However, concurrent use of CYP-inducing medications may decrease the half-life to ~9
hours.(30921021)
monitoring – valproic acid level
Periodic monitoring of valproic acid may be helpful if the dose is in question (e.g., patients on higher doses, obesity, questionable oral absorption, or drug-drug interactions).(28833346)
Valproate should always be measured as
a trough level, immediately before a dose.
The therapeutic valproic acid level for status epilepticus is ~80-150 mg/dL. However, the optimal dose range for critically ill patients remains unclear. Among critically ill patients with an increased fraction of free valproic acid, a somewhat lower total valproate level might be appropriate.
The free valproate level should ideally be 5-25 ug/ml. However, this
is a send-out test that is only obtained if toxicity is suspected.
monitoring – ammonia level & liver function testing
Ammonia levels don't need to be checked unless there is a concern for encephalopathy.
Ammonia levels are often moderately elevated among patients on valproic acid (e.g., in the range of ~50-100 ug/dL). Mild ammonia elevation doesn't necessarily mandate discontinuation of valproate. Administration of oral
L-carnitine should be considered for these patients, to prevent worsening hyperammonemia (e.g., 1,000 mg/day divided q6-q8, possibly titrating up to 3000 mg/day 📖).
Elevation of transaminases may occur. Thus, periodic monitoring of liver function tests may be reasonable.
Further discussion of valproic acid as a sedative agent:
📖
fosphenytoin
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dosing 💊
(#1) Loading dose is 20 PE/kg (max 1,500) at 150 PE/min. If still seizing may give an
additional 5 PE/kg (max 500).
(#2) May check a serum level 2 hours after the load.
Practice varies between centers regarding to how often this is measured. A level should especially be considered for patients with unusual pharmacokinetics (e.g., morbid obesity).
The target is a total phenytoin level of 15-20 ug/mL, or an estimated free phenytoin level of 1.5-2 ug/mL after albumin correction (more on this
below).(34798964; 34619776)
If the level is below target, then an additional partial load may be administered. Partial loading dose is equal to (wt in kg)(0.7)(target phenytoin level – current phenytoin level).(Albin 2022)
(#3) Maintenance
dose is 5-7 PE/kg/day in 2-3 divided doses (e.g., ~100 mg q8hr).
Morbid obesity: May dose based on adjusted body weight 🧮. (Torbey, 2019)
Note: FOSphenytoin is the prodrug of phenytoin. It is more water soluble and does not require to be dissolved in propylene glycol. It is dosed in terms of the equivalent phenytoin dose (“phenytoin
equivalents” or “PE”).
⚠️ Always order FOSphenytoin for intravenous loading doses. Phenytoin is dissolved in propylene glycol and can lead to severe tissue necrosis (“purple glove syndrome”) if it extravasates.
contraindications
Pregnancy.
Hepatic or renal dysfunction.
Hypotension, bradycardia, or cardiac conduction abnormalities.
Seizures due to cocaine, local anesthetics, lindane,
or theophylline (not generally useful for toxicological seizures).
Absence or myoclonic seizures may be exacerbated by phenytoin. Valproate or levetiracetam are more effective for these seizure types.(34798964)
Phenytoin is cleared by CYP 2C9 and 2C19, leading to drug-drug interactions. For example, amiodarone, fluoxetine, isoniazid, and azole antifungal agents may reduce the
metabolism of fosphenytoin.(35393968)
Phenytoin is a potent inducer of CYP 2C9, 2C19, and 3A4 – resulting in numerous drug-drug interactions.(34300194)
Numerous drug-drug interactions (phenytoin is a CYP-inducer).
Stevens-Johnson syndrome, DRESS syndrome.
Pancytopenia.
Drug fever.(Shutter, 2019)
Sedation. Sedating effects might inhibit functional neurological recovery in some disorders.(Shutter, 2019)
A
paradoxicalincrease in seizures may occur with concentrations >30 mg/L.(30921021)
indications & general comments
Traditionally fosphenytoin was a front-line agent in status epilepticus. However, with the emergence of levetiracetam there are now numerous reasons not to use fosphenytoin as a front-line
agent:
(#1) Fosphenytoin causes numerous drug-drug interactions (especially with valproate 📖)
(#2) Fosphenytoin has numerous contraindications (e.g., pregnancy, hepatic dysfunction, renal dysfunction). In emergent situations, it may not be obvious whether the patient has these conditions.
(#3) Fosphenytoin can cause severe bradycardia or hypotension
(if given too rapidly, or to patients with cardiac comorbidity). In some situations, slowing down the infusion may be adequate to stabilize the patient and continue medication administration.
(#4) Fosphenytoin may cause other complications including Stevens-Johnson Syndrome, pancytopenia, phlebitis, and drug fever.
(#5) Monitoring phenytoin levels in the ICU is is difficult (unless your lab provides rapid turnaround time on free phenytoin levels). Elevated phenytoin
levels may cause delirium.
(#6) Zero-order kinetics may increase the potential for toxicity – more on this below.(29666958)
(#7) Phenytoin is ineffective against generalized myoclonic or absence seizures, and may even exacerbate these.(35393968) Thus, phenytoin is a more
narrow-spectrum antiseizure medication than levetiracetam, phenobarbital, or valproic acid (which are effective against myoclonic seizures).
pharmacology, mechanism of action
A 1:1 conversion is often used to convert from PO to IV administration, but oral bioavailability is variable (so levels should be followed when transitioning route). Enteral phenytoin absorption is decreased when administered with tube
feeding.(34697528) Various options to avoid this issue:
Intravenous fosphenytoin avoids the issue entirely.
Convert nutritional administration to bolus feedings, with the administration of phenytoin between bolus feeds. More on bolus feeding here: 📖
Use
continuous tube feeding, but hold tube feeds for two hours before and after administration of phenytoin.
Mechanism of action: Prolongs the recovery of activated voltage-gated sodium channels, preventing repetitive neuronal firing.(34221552)
Pharmacology: Fosphenytoin is converted by the body into phenytoin, the active drug. Phenytoin is metabolized in the liver via CYP
2C9 and to a lesser extent 2C19, with a half-life of ~12-29 hours. However, phenytoin's metabolism is saturable so as levels rise its half-life stretches out – this promotes drug accumulation at higher doses (figure below).(30921021)
Consider dose reduction in hepatic failure.
monitoring
The trough levels should be followed.
Free phenytoin levels are the ideal parameter to follow, since this reflects the active drug concentration.
The target free phenytoin level is 1-2 ug/mL.
Unfortunately,
free phenytoin level is generally a send-out test with slow turnaround time. If free phenytoin levels aren't rapidly available, they may be correlated with an albumin-corrected total phenytoin level. The free phenytoin level should be ~10 times lower than the albumin-corrected phenytoin level. If levels don't correlate well, then consider either dosing solely based on free phenytoin levels (if these can turn around rapidly enough) or avoiding phenytoin altogether.
Total phenytoin level:
The target total phenytoin level is ~10-20 ug/mL (and ideally 15-20 ug/mL in status epilepticus).(33176370; Albin 2022)
Causes of disproportionately elevated free phenytoin level (when compared with the total phenytoin level) are listed
below.(30921021) Most critically ill patients will have one or more of these factors, so the total phenytoin level often isn't very accurate in the ICU.
Renal dysfunction.
Low albumin (phenytoin is highly protein bound).
Medications that compete with phenytoin for binding to albumin (e.g., valproic acid).
Hepatic
dysfunction.
Pregnancy or old age.
Critical illness.
Correcting the total phenytoin level:
The most accurate equation to estimate the free phenytoin in critically ill patients appears to be the Barra equation: 📄 (32049893)
Estimated
Free phenytoin = 1.69 + 0.139(Total phenytoin in mcg/ml) – 0.008(Age) – 0.424(Albumin in g/dL) + 0.01(BUN in mg/dL) + 0.288 [Critically Ill (yes, 1; no, 0)]
This equation may be inaccurate in the context of medications that compete with albumin binding (e.g., valproic acid).(Albin 2022)
interactions between phenytoin & valproate
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contents)
medication interactions include:
Effect on phenytoin:
Valproate inhibits CYP2C9, which leads to an accumulation of phenytoin. Based on the saturable metabolism of phenytoin, this may cause phenytoin levels to gradually drift upwards over time (discussed in the section above).
Valproate competes with phenytoin for binding to albumin, which increases the free level of
phenytoin. This renders therapeutic monitoring of total phenytoin levels inaccurate.(33896531)
Phenytoin accumulation as well as an increased free fraction of phenytoin may tend to cause phenytoin toxicity.(24381240)
Effect on valproate:
Phenytoin may induce
the metabolism of valproate, thereby lowering valproate levels.
Phenytoin competes with valproate for binding to albumin, potentially increasing the free level of valproate. This may impair monitoring based on total serum valproate levels.
approach to the combination of phenytoin & valproate:
As a general rule, this combination of agents should be avoided.
⚠️ Note that both phenytoin and valproic acid may cause adverse neurologic effects at supratherapeutic levels. Phenytoin and/or
valproic acid toxicity may be insidious, since symptoms will initially be attributed to other causes (e.g., nonspecific ICU delirium).
If phenytoin and valproate are used together, free levels of both medications should be closely monitored. Unfortunately, the majority of hospitals lack the capability to measure free drug levels of both agents
rapidly.(121944)
lacosamide
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dosing 💊
Load: Typically 400 mg IV over 5 minutes (although it might be ideal to use
weight-based dosing of 10 mg/kg up to a maximal dose of 500 mg).(33664203; 35605086) If still seizing, may give an additional 5 mg/kg (max 250 mg) or simply 200 mg, over 5 minutes.(33896531;
29733464)
Maintenance: Typically 200 mg IV q12hr. However the dose range may extend up to 600 mg/day, divided q12hr or q6hr.(33896531)
Dose-adjustment:
Renal dysfunction: If GFR<30 ml/min, reduce dosage by 25%. Consider supplementing
with up to 50% of dose after a 4-hour dialysis session.
Hepatic dysfunction: Lacosamide isn't recommended in severe hepatic dysfunction.
contraindications
Pre-existing heart block or conduction system disease (e.g., second degree AV block).
Underlying proarrhythmic conditions (ventricular tachycardia is reported in some cases).
May exacerbate seizures in Lennox-Gastaut syndrome.(Albin 2022)
side effects
Atrioventricular (AV) block causing bradycardia.
Hypotension.
Common adverse events include nausea, emesis, headache, dizziness, diplopia, and sedation. Adverse events may be more likely at higher doses, or when lacosamide is combined with other sodium-channel blocking antiseizure medications.(30921021)
indications & advantages
Newer antiseizure medication.
Safe, with minimal drug interactions. Generally well tolerated and easy to use. Efficacy in super-refractory status epilepticus appears similar to other antiseizure medications.(34221552)
May have greater efficacy and superior tolerability if combined with antiseizure medications that
have a different mechanism of action.(30921021)
pharmacology, mechanism of action
Oral bioavailability is 100%., allowing a 1:1 conversion PO:IV.
40% is excreted unchanged in the urine, with some hepatic inactivation as well (via CYP 2C9, 3A4, and 2C19).(30921021) Dose should be reduced in renal failure as outlined above.
🏆 Lacosamide is somewhat unique among anti-seizure
medications in terms of its dual elimination by both kidneys and liver. This may tend to make drug levels more resistant to small changes in the function of either organ.
phenobarbital
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dosing 💊
Load:
15-20 mg/kg at 50-100 mg/min.(34221552) If still seizing, additional doses may be added for cumulative total dose of 30 mg/kg.
15 mg/kg was used in the VA Cooperative trial, so this dose is supported by evidence among patients who are not intubated. 📄
(9738086)
May check level 2 hours after loading dose to ensure adequate level.(Albin 2022)
Maintenance: 1-3 mg/kg/day given daily or divided q12hr (e.g., 50-100 mg IV q12hr).(33896531; 34300194,
34798964)
For every 1 mg/kg of phenobarbital administered, the serum phenobarbital level will rise by roughly ~1.5 mg/L (e.g, 10 mg/kg will increase the phenobarbital level by 15 mg/L).
Trough levels may be monitored to ensure appropriate dosing, with a target of ~15-40 mg/L (more on this below).
contraindications
Porphyria
Prior chronic phenobarbital use.
Pregnancy.
Drug interaction with another critical medication (see section below).
side effects & drug interactions
Somnolence (long half-life may increase risk of prolonged sedation.)
Respiratory suppression (although this is typically associated with much higher doses of phenobarbital than 20 mg/kg).
Hypotension.
Phenobarbital is metabolized by CYP2C9 and 2C19,
which may lead to drug-drug interactions
Phenytoin may reduce phenobarbital metabolism (due to competition for hepatic metabolism).
Valproate may reduce phenobarbital metabolism; consider reducing the phenobarbital dose by 50%.(Torbey, 2019)
Phenobarbital is an inducer of CYP 1A2, 2C9, and 3A4, which leads to numerous drug-drug interactions.(33176370)
It may be necessary to adjust the dose of other medications that the patient is on (including phenytoin and valproate).
indications & advantages
Not usually a front-line agent, but this remains an effective agent:
(1) Arguably the preferred antiseizure medication for alcohol withdrawal seizures.📖
(2) Effective in
refractory status epilepticus.(30159873)
(3) Useful super-refractory status epilepticus, to assist in weaning patients off a pentobarbital coma.
Phenobarbital (15 mg/kg) was found to be equally effective as compared to lorazepam (0.1 mg/kg) as first-line therapy for status epilepticus in the VA-Cooperative trial. Thus, phenobarbital may be more effective and better tolerated
than is commonly recognized. 📄 (9738086)
Usual therapeutic target is a trough level of ~15-40 mg/L
although some authors recommend targeting 20-50 mg/L.(34798964) (More on phenobarbital levels here: 📖)
Mostly metabolized in the liver (CYP2C9 > 2C19), but ~25% may be excreted unchanged in
urine.(30921021) Half life is typically ~80 hours, but may vary from ~50-140 hours.(Torbey, 2019)
Consider dose reduction in hepatic dysfunction.
propofol
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dosing
💊
Load: 2 mg/kg IV bolus (up to 200 mg). May repeat q3-5 minutes if hemodynamically tolerated, to a total dose of 10 mg/kg.
Infuse: 30-200 mcg/kg/min. However, avoid >83 mcg/kg/min for prolonged periods of time to reduce the risk of propofol infusion syndrome.
💡 Consider early initiation of enteral nutrition to reduce the risk of propofol infusion
syndrome.(33480193)
contraindications
Severe hemodynamic instability
Hypertriglyceridemia
side effects
Hypotension that often requires a vasoconstrictor (e.g., norepinephrine) to balance out the vasodilatory effects of propofol. The need for moderate doses of norepinephrine to allow administration of
propofol is not a contraindication to the ongoing use of propofol.
Occasional bradycardia.
Hypertriglyceridemia.
Propofol infusion syndrome.
indications & advantages
Preferred agent, easy to titrate.
If abruptly stopped, patients may have rebound seizure.
pharmacology, mechanism of action
Mechanism of action: Stimulates inhibitory GABA receptors, inhibits NMDA
receptors, and may reduce calcium influx through slow calcium channels.(34300194, 33480193) A more broad-based mechanism of action might explain why propofol retains potency over time, whereas midazolam (which solely works via GABA receptors) becomes less effective over time.
Triglyceride levels should
be monitored q48hr-q72hr.
ketamine
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dosing 💊
Loading dose: Give successive boluses of 1-2 mg/kg every 5 minutes, up to a total of ~5 mg/kg cumulative dose.
Maintenance
infusion: The infusion dose range is 1-7.5 mg/kg/hr.(33896531, 34221552) Doses <1 mg/kg/hr do not appear to be effective.(33664203)
Titrate based on EEG.
For break-through seizures, may re-bolus with ketamine
and increase the infusion rate.
The EEG pattern related to clinical efficacy with ketamine is heterogeneous. Cessation of seizures may be a more appropriate therapeutic target than burst-suppression.(33480193)
contraindications
Inadequate local supply of ketamine.
Dangerously uncontrolled hypertension (may be exacerbated by
ketamine).
side effects
May increase blood pressure and heart rate.
May exhaust hospital's ketamine supply.
Hypersalivation.
indications & advantages
Overall and excellent and under-appreciated anti-epileptic agent. Ketamine is emerging as a preferred agent to control super-refractory status epilepticus.
Ketamine combines nicely with propofol, midazolam, or barbiturates
(propofol, midazolam, or barbiturates stimulates the GABA receptor, whereas ketamine inhibits the NMDA-type glutamate receptors).
Advantages of ketamine for super-refractory status epilepticus, as compared to barbiturate coma:
Ketamine is more hemodynamically stable.
Ketamine has a shorter half-life, providing more flexibility in adjusting the infusion.
Ketamine can be rapidly up-titrated to determine efficacy (and, if not working, another agent may be used).
NMDA-receptor antagonists often remain effective in ongoing status epilepticus (whereas benzodiazepines, barbiturates, and phenytoin lose potency over time as the seizure evolves).(33896531)
pharmacology, mechanism of action
Mechanism: NMDA antagonist.
Half-life of 2-3
hours.(33480193)
Hepatic metabolism, with no dose adjustment in renal failure. Consider dose reduction in hepatic impairment.(33896531)
midazolam infusion
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dosing
💊
Load: 0.2 mg/kg. May repeat this q5-10 up to 2 mg/kg total dose.
Infuse: 0.05-2 mg/kg/hr.
contraindications
Use caution in obese patients and patients with renal insufficiency, who may accumulate midazolam and clear it very
slowly.(34221552)
side effects
Delirium, drug accumulation leading to delayed extubation (although to a lesser extent than pentobarbital).
Hypotension may occur at higher doses.(34221552)
indications & general comments
Widely
available.
Will hinder the ability to rapidly awaken and wean patients off ventilation. For most patients, propofol may be a preferred anesthetic since this preserves the ability to awaken and re-evaluate patients neurologically.
pharmacology, mechanism of action
Mechanism: Binds inhibitory GABA receptor, increases frequency of channel opening.
Midazolam accumulates over time, causing the half-life to extend over time
(context-sensitive half-life).
Midazolam is hepatically metabolized into an active metabolite (1-hydroxy-midazolam), which is subsequently excreted by the kidneys. Consider dose reduction in renal or hepatic impairment.(33896531)
Ongoing use causes resistance (tachyphylaxis).
pentobarbital coma
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dosing 💊
⬟ Load: 5-15 mg/kg at 50 mg/min. May provide additional doses if seizures continue, up to a maximal total loading dose of 25 mg/kg.
⬟ Infuse: Start at 1 mg/kg/hr, then titrate between 0.5-5
mg/kg/hr.(34300194) Titrate based on EEG as described below.
contraindications
Hemodynamic instability
Porphyria
side effects
Hypotension (patients will commonly require vasopressor support).
Ileus (may progress to bowel pseudoobstruction and perforation).
Ventilator-associated pneumonia
(VAP).(34300194)
Thrombocytopenia.
Persistent coma (half-life is 15-60 hr!).
Very sluggish agent to titrate; obligates patient to prolonged intubation and long ICU stay.
Propylene glycol toxicity may cause metabolic acidosis.
indications & comments
⬟ Last-line agent for super-refractory status epilepticus.
⬟ Pentobarbital is almost uniformly effective. However, the problem is that it has many side-effects (including hypotension, propylene glycol toxicity) and an incredibly sluggish half-life. Thus, putting a patient into a pentobarbital coma commits them to a 1-2 week ventilator course.
Withdrawal of life-sustaining therapy subsequent to induction of a pentobarbital coma is ethically questionable. Ideally, pentobarbital should be reserved for
patients who are committed to aggressive support. If families wish to trial a short course of intubation (e.g. 1-2 days), then a ketamine infusion would be more appropriate.
In a small RCT of propofol versus barbiturates, there was a similar rate of seizure control, but patients treated with barbiturates had a substantially longer duration of mechanical ventilation.(20878265)
pharmacology, mechanism of action
Mechanism of action: Stimulates inhibitory GABA receptors, inhibits AMPA-type glutamate receptors. This is important, because enhanced AMPA-receptor activity is one mechanism involved in refractory status epilepticus.(35001380)
Half life may vary between 15-50 hours, in a dose-dependent fashion.(Torbey
2019)
Hepatic metabolism to inactive metabolites. Consider dose reduction in hepatic impairment.(33896531) Inducer of CYP2A6, with auto-induction of its own metabolism.(33176370)
monitoring
(1) Continuous EEG monitoring is
necessary for all patients undergoing pentobarbital coma. If your center does not have continuous EEG monitoring, the patient will require transfer to a center that does.
Typically the infusion is titrated to achieve burst suppression.
If the patient develops a completely flat EEG tracing, consider reducing the dose or holding the infusion entirely.
(2) Target serum level 10-20
ug/mL.(33176370) However, this is often a send-out laboratory test, so it's not helpful for immediate dose titration.
topiramate
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dosing in refractory status epilepticus
💊
Load: 300-800 mg PO.(31766004)
Maintenance: 200-500 mg BID PO,(31766004) or possibly up to 1,600 mg/day in 2-4 divided
doses.(34619776) Doses above 400 mg/day usually don't improve seizure control, but they are associated with increasing incidence of side effects. (Louis 2021)
No IV form.
contraindications
Coadministration with valproic acid may increase the risk of hyperammonemia (topiramate inhibits glutamine synthetase, leading to reduced ammonia
metabolism).(33176370)
May be a reasonable add-on drug, but little experience in refractory status epilepticus.
Seems to have a
fairly good side-effect and interaction profile.
pharmacology, mechanism of action
Half-life ~21 hours. Mostly (~70%) eliminated unchanged by the kidneys. Some metabolism by the liver, via non-CYP pathways.
Dose reduce in renal dysfunction, consider reduction in hepatic dysfunction.
Affects several receptor systems (GABA, calcium channel inhibition, sodium channel blockade, AMPA/kainate glutamate receptor inhibition).
perampanel
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dosing for intubated patient in refractory status epilepticus 💊
The loading dose of 32 mg is often used.(31766004;
31565443) This may be followed with a maintenance dose of ~8-12 mg/day.(33830480) A pharmacokinetically superior regimen described in the literature is 36 mg on day #1, 24 mg on day #2, and then 12 mg/day.(35605086)
Perampanel has a half-life of 105 hours (4.3 days), which is similar to the half-life of phenobarbital. Thus, simply starting 6-12 mg/day without a loading dose won't achieve a steady-state drug level for more than a week.
Consider a reduced maintenance dose in patients with mild-moderate hepatic impairment.(33830480)
contraindications
Interactions with other antiseizure medications: Phenytoin, oxcarbazepine, carbamazepine, topiramate, midazolam.
Not recommended in severe hepatic dysfunction, or renal dysfunction with GFR < 30 ml/min.(33830480)
side effects
Primary side-effect of concern is psychiatric (aggression, psychosis, suicidal/homicidal
ideation).(33830480) Most other side-effects are relatively mild (dizziness, somnolence, headache, ataxia).(35393968)
DRESS (drug reaction with eosinophilia and systemic symptoms).
Perampanel accelerates metabolism of levonorgestrel, a component of some oral contraceptives.
indications
& advantages
Perampanel may be utilized for focal seizures, generalized tonic-clonic seizures, and possibly generalized myoclonic seizures.(35393968)
Available evidence regarding the use of perampanel for super-refractory status epilepticus is encouraging. However, little evidence is
available.(30613951, 31565443)
pharmacology, mechanism of action
Perampanel is a selective, noncompetitive AMPA-type glutamate receptor antagonist. This is a unique mechanism of action, which may be effective in situations where other medications have failed.
Perampanel is only
available enterally, with excellent bioavaiability.
Clearance is predominantly via hepatic metabolism with a half-life of 105 hours (CYP3A4 > 3A5). Hepatic metabolism may be induced by phenytoin, carbamazepine, oxcarbazepine, or topiramate. However, 22% may be cleared by the kidneys.
clobazam
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dosing
💊
10-40 mg/day in two divided oral doses.
contraindications
Severe hepatic dysfunction.
Impaired respiratory drive (e.g., sleep apnea or obesity hypoventilation syndrome).
Narrow-angle glaucoma.
side effects
Sedation and respiratory suppression (similar to other benzodiazepines,
although less prominent).(30921021)
indications & advantages
Clobazam acts similarly to other benzodiazepines, albeit perhaps causing less sedation.
Lack of an IV formulation means that clobazam is not useful for initial seizure control. However, clobazam could have a potential role for some patients to facilitate weaning off anesthetic
infusions.
pharmacology, mechanism of action
Clobazam is a 1,5-benzodiazepine (unlike traditional 1,4-benzodiazepines). Similar to other benzodiazepines, clobazam stimulates the GABA-A receptor. However, unlike traditional benzodiazepines, clobazam is a partial agonist. Clobazam may also be more selective for GABA-A receptors, thereby reducing cognitive side-effects.
Bioavailability is 100%, with a peak plasma time of
0.5-4 hours.
Clobazam is metabolized in the liver via the CYP system (primarily CYP3A4, and also CYP2C19 and CYP2B6) into N-desmethylclobazam (an active metabolite with about 1/5 the potency of clobazam). N-desmethylclobazam is subsequently metabolized via CYP2C19.
Clobazam has a half-life of ~40 hours, whereas N-desmethylclobazam has a half-life of ~80 hours. Given these extended half-lives, steady-state effects may not occur until 5-9 days after initiation of
therapy.
Consider dose reduction in hepatic dysfunction.
Clobazam is an inhibitor of CYP2D6 and a weak inducer of CYP3A4. This may cause an unpredictable increase in valproic acid levels.
thiamine
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dosing 💊
If concern for Wernicke’s: 500 mg IV q8hr
To prevent Wernicke’s: 100 mg IV daily
indications
Traditional component of status epilepticus management (due to concerns regarding undiagnosed thiamine deficiency).
Thiamine deficiency doesn’t usually manifest with seizure, but this is possible.
pyridoxine
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dosing 💊
180-600 mg daily (PO or IV).
In INH, gyromitra mushroom toxicity, or chronic oral hydralazine use very high doses are used (e.g., 5 grams IV). This dose may be repeated after thirty minutes.(LaHue 2021)
indications & advantages
Safe, may help some patients. Deficiency
occurs and may lower seizure threshold.
Most useful in:
INH poisoning.
Gyromitra mushroom toxicity.
Alcoholism/malnutrition.
Chronic critical illness.
Patients on oral hydralazine (which may cause pyridoxine deficiency).
Pyridoxine administration might also help reduce the behavioral side-effects of levetiracetam, perhaps at a dose of 100 mg PO TID.(Albin 2022;
33823377)
ketogenic diet
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This may be effective, even for super-refractory status epilepticus. (24453083,
30638692)
This is generally safe (the risk/benefit ratio is arguably superior to most antiseizure medications).
Nutritional ketosis can be done in patients with Type-I diabetes, although is more complicated and requires closer monitoring.
It is contraindicated in patients with certain mitochondrial disorders, porphyria, or fatty acid oxidation deficits.
The combination of a ketogenic
diet with propofol should be avoided, as this may increase the risk of propofol infusion syndrome.(34300194)
Main barriers are logistic:
Ketogenic tube feed formulation is required (many hospitals may lack this).
Drugs formulated in D5W must be avoided.
Lamotrigine may impair the ability to achieve
ketosis.(33176370)
Requires buy-in from pharmacy, who will need to calculate all the carbohydrate content of the patient's medications and determine if ketosis is achievable.
podcast
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questions & discussion
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To keep this page small and fast, questions & discussion about this post can be found on another page
here.
Avoid leaving the bedside of a patient in generalized convulsive status epilepticus until the seizures are controlled. This should nearly always be possible within <30
minutes (using intubation and high-dose ketamine if necessary).
ALL patients with status epilepticus should be treated with a conventional antiseizure medication (e.g. levetiracetam), regardless of whether the seizure responds to benzodiazepine. If the benzodiazepine works, you still need to follow up with an antiseizure medication for longer term efficacy.
Avoid inadequate dosing of levetiracetam (recent guidelines recommend 60 mg/kg, up to 4.5 grams).
Avoid
inadequate dosing of benzodiazepine up-front (0.1 mg/kg might be ideal; anything below 4 mg lorazepam is woefully inadequate).
Beware of using paralytic for intubated patients with convulsive seizure – this makes things look nice but doesn't prevent brain damage from the seizure.
Don't fall prey to intubatophobia: the fear that intubating seizure patients may make them worse. On the contrary, early airway management facilitates definitive seizure control and
prevents complications (e.g. aspiration, rhabdomyolysis).
Acknowledgement: Thanks to Dr. Richard Choi (@rkchoi) for thoughtful comments on this chapter.
Guide to emoji hyperlinks
Going further
PulmCrit
Rapid-sequence termination (2014)
Resuscitationist's guide to status
All conventional 2nd line anti-epileptics are equally bad: ESETT trial
EMCrit podcast #155: Status epilepticus with Tom Bleck
Status Epilepticus (First10EM, Justin Morgenstern)
Status Epilepticus (EMCases, Anton Helman)
Status Epilepticus
(LITFL, Chris Nickson)
supplemental media
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What is the best treatment for status epilepticus?
BENZODIAZEPINES. The benzodiazepines are some of the most effective drugs in the treatment of acute seizures and status epilepticus. The benzodiazepines most commonly used to treat status epilepticus are diazepam (Valium), lorazepam (Ativan), and midazolam (Versed).
What drug is IV used for status epilepticus?
Diazepam. Diazepam is the first benzodiazepine used for the treatment of epilepsy and SE. Highly lipophilic and rapidly enters the brain, diazepam can be administered intravenously as a bolus of 0.15–0.2 mg/kg up to 10 mg.
Why is intravenous diazepam used in the treatment of status epilepticus?
Diazepam is frequently used for treatment of SE, because it can be delivered either intravenously or rectally. However, the effectiveness of diazepam in terminating seizures is thought to be inferior to that of other benzodiazepines, especially when given rectally.
