CONTENTS
- Getting started:
- Diagnosis & definition
- Treatment overview
- Approach to medication selection
- Antiseizure medications
- Anesthetics
- Other medications
- Other topics
- Podcast
- Questions & discussion
- Pitfalls
diagnostic evaluation
history
- 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).
- Urinalysis.
- Toxicology workup as indicated (e.g., salicylate level, 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 angiography may be considered if there is suspicion for stroke.
- CT perfusion may reveal focal areas of cortical hyperperfusion. 📖
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
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.
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).
infectious / inflammatory
- CNS infection (meningitis, encephalitis, brain abscess).
- Autoimmune encephalitis (especially limbic encephalitis 📖).
- Lupus, vasculitis.
- Sepsis with systemic inflammation (may reduce seizure threshold).
vascular
- Remote stroke that caused residual epileptogenic focus.
- Acute stroke (ischemic > hemorrhagic).
- CVT (cerebral venous thrombosis).
- Hypertension-related: PRES 📖, Eclampsia 📖.
traumatic brain injury
- Contusions.
- Subarachnoid hemorrhage.
- Subdural hematoma.
- Epidural hematoma.
drugs
- (1) Nonadherence with antiseizure medication, changes in regimen, drug-drug interactions.
- (2) Medications that lower seizure threshold, for example:
- Psychiatric medications (antipsychotics; lithium; antidepressants, especially bupropion or tricyclics).
- Local anesthetics (e.g., lidocaine).
- Antimicrobials (e.g., beta-lactams especially imipenem; quinolones; metronidazole; acyclovir; ganciclovir; isoniazid).
- Antihistamines.
- Antiquated analgesics (tramadol, meperidine, propoxyphene).
- Chemotherapeutics & immunomodulators (e.g., amsacrine, asparaginase, blinatumomab, busulfan, carmustine, chlorambucil, cisplatin, cyclophosphamide, cyclosporine, cytarabine, dacarbazine, etoposide, fludarabine, 5-fluorouracil, gemcitabine, ifosfamide, methotrexate, nelarabine, paclitaxel, tacrolimus, thalidomide, vincristine).(33273175; 32487905)
- Theophylline.
- 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
- 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.
- “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).
- Cerebral Amyloid Angiopathy spells (Transient Focal Neurologic Episodes).
- Pseudoseizure (see the section below).
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).
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
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.
- 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).
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 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).
Further discussion of the selection and dosing of antiepileptic agents is below 📖.
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 stimulates 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 (e.g., phenylephrine or norepinephrine).
- 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.
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.
causes of NORSE
- ~40% Non-paraneoplastic autoimmune (e.g., anti-NMDA encephalitis).
- ~30% Paraneoplastic.
- ~20% Infectious.
management:
- Early empiric therapy with high-dose steroid, plasma exchange, and/or IV immunoglobulin may be considered.(33896531)
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)
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).
- 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.
overall strategy for refractory status epilepticus
- Both antiseizure medications and anesthetic infusions should be simultaneously escalated until seizure control is achieved.
- A common mistake is to focus excessively on anesthetic infusions while forgetting to escalate antiseizure medications.
- Maximize the dose of each antiseizure medication. For status epilepticus it's generally preferable to start with high doses to achieve seizure control.
- 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.
antiseizure medication(s)
general principles
- (#1) 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.
- (#2) It's 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)
- (#3) Avoid the combination of phenytoin and valproic acid (since these interact in a variety of ways 📖).
The following approach is reasonable for most patients, in the absence of contraindications to these agents. However, it's not necessarily superior to various other approaches.
#1) front line therapy: 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).
#2-3) second & third-line therapies: valproic acid & lacosamide
- These agents may be added in either order.
- Valproic acid 📖
- Valproic acid is a traditional agent that is a good option for most patients.
- Valproic acid and fosphenytoin interact with one another, so only one of these can be utilized. 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) Valproic acid also has the advantage of synergizing better with lacosamide.
- Lacosamide 📖
- Lacosamide is a newer agent that is generally safe and easy to use, with few drug-drug interactions. This may make it easier to achieve therapeutic drug levels rapidly.
- The efficacy of lacosamide is less well established than valproic acid.
#4) 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.)
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)
continuously infused anesthetic agent(s)
front 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 superior side-effect profile compared to pentobarbital coma.
- 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).
third line: pentobarbital coma 📖
- 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.
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, 36333031)
- 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:
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).
- Thrombocytopenia and/or leukopenia (rare).(29666958)
- 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.
- Levetiracetam is 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)
dosing 💊
dosing for status epilepticus
- (#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 1-2 hours after the load.(Albin 2022; 36333031) 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:
- 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.
dosing for refractory agitated delirium
- (1) Load with 20-25 mg/kg IV.(10372567, 28833346)
- (2) Initial maintenance dose is 20 mg/kg daily in divided doses (studies usually describe 10 mg/kg q12hr, but smoother pharmacokinetics may be achieved with q8hr dosing).(28833346, 27693975)
- (3) The maintenance dose may be gradually up-titrated to effect as needed, with a maximal dose of 60 mg/kg daily in divided doses (e.g., 30 mg/kg q12hr).
- The half-life of valproic acid is ~14 hours, so drug levels won't reach steady state until a few days after a dose change. There are two ways to adjust dosing:
- (i) The dose can be escalated relatively rapidly (e.g., on a daily basis), but be aware that levels will continue to rise for a few days following dose escalation! Therefore, once a therapeutic effect is reached, it might be sensible to slightly reduce the daily dose.
- (ii) If the valproic acid level is very low and a substantial dose escalation is needed, an additional re-loading dose may be utilized. With q8hr dosing, the re-loading dose should be about three times the dose escalation (e.g., if increasing from 500 mg TID to 700 mg TID, an additional re-loading dose would be 3×200=600 mg). 🌊
- After patients are improving and delirium has lifted, valproate may be gradually weaned off. Efforts should be made to avoid prolonged administration (especially discontinuation prior to discharge from the hospital).
dosing for alcohol withdrawal
- For alcohol withdrawal, 20 mg/kg daily in divided doses (10 mg/kg BID) has shown efficacy in some small studies. (11916372, 32794143)
- A loading dose of 20-25 mg/kg makes sense, to accelerate reaching therapeutic levels faster.
- Overall, this dosing strategy is similar to the approach to agitated delirium above.
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.
- Target level:
- Status epilepticus: The therapeutic valproic acid level is ~80-150 mg/dL.
- Psychiatric / agitation use: The therapeutic valproic acid level for bipolar disorder is 50-125 mg/L.
- Unfortunately, the optimal dose range for critically ill patients remains unclear. Among critically ill patients with an increased fraction of free valproic acid (e.g., due to hypoalbuminemia), a somewhat lower total valproate level could 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.)
ammonia level
- 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 3,000 mg/day 📖).
liver function testing
- Elevation of transaminases may occur. Thus, periodic monitoring of liver function tests may be reasonable.
contraindications, drug interactions, side effects
contraindications
- Pregnancy.
- Severe liver disease.
- Thrombocytopenia (valproic acid may cause mild thrombocytopenia in ~1/3 of patients).
- Urea cycle disorder or mitochondrial disorders that cause hyperammonemia.
- History of hyperammonemia.
drug interactions
- 🛑 Avoid combining valproic acid with fosphenytoin 📖, carbapenems, lamotrigine, or topiramate.(33896531)
- Valproic acid may increase free levels of warfarin, so monitor the INR closely.
- Clobazam may increase valproic acid levels, due to inhibition of metabolism.
side effects
- Hyperammonemia, encephalopathy, sedation.
- Stevens-Johnson syndrome (rare).
- Drug reaction with eosinophilia and systemic symptoms (DRESS).
- SIADH.
- Idiosyncratic pancreatitis, hepatotoxicity (with hepatic failure largely restricted to children). (Louis 2021)
- Impaired platelet aggregation, dose-related thrombocytopenia.
- 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 and advantages
use in status epilepticus
- 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.
- Valproic acid may be especially useful in myoclonic or absence status.(36333039)
- 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.
use in refractory agitated delirium
- Benefits include:
- Minimal cardiac or respiratory effects (allowing it to be used regardless of intubation status).
- No issues with tolerance or withdrawal.
- Anti-epileptic properties.
- Theoretical and case series evidence suggest that valproate might be helpful to reverse agitated delirium.(32273047) Particularly, it may be effective in agitated delirium refractory to other therapies (e.g., antipsychotics).
- Drawbacks:
- Valproate often takes a couple days to cause improvement (although this may be accelerated by using a proper loading dose).
- Periodic monitoring of drug levels, liver function tests, and ammonia is advisable.
- Valproic acid may be useful as a treatment for agitated delirium, especially:
- Refractory agitation/delirium which has failed to respond well to other agents.
- Patients with a history of borderline personality.
- Patients with a history of traumatic brain injury. (28833346)
use in alcohol withdrawal
- Discussed further here: 📖
pharmacology and mechanism of action
- Valproic acid has a broad mechanism of action, including:(34300194, 32794143)
- Prolonged recovery phase of voltage-gated sodium channels.
- Enhanced GABA signaling.
- Inhibition of T-type calcium channels.
- Inhibition of NMDA receptors.
- 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)
- For administration to critically ill patients, the immediate-release formulations are more reliably and rapidly absorbed.
- ⚠️ Enteral administration may increase gastrointestinal side-effects, especially with liquid formulations.
- 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).
- 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)
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:
- 5-7 PE/kg/day in 2-3 divided doses (e.g., ~100 mg q8hr).
- 200-600 mg/day in 2-3 divided doses.(36333031)
- 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 & drug interactions
- 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)
side effects
- Hypotension, bradycardia.
- Concentration-dependent neurologic side-effects: Nystagmus, ataxia, dysarthria, lethargy, tremor, delirium, and coma.(34221552)
- 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 paradoxical increase in seizures may occur with concentrations >30 mg/L.(30921021)
- Pulmonary side-effects are uncommon. However, phenytoin can cause hypersensitivity pneumonitis, eosinophilic pneumonia, or LIP (lymphocytic interstitial pneumonia).(35131079)
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.
- Hypoalbuminemia (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)
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)
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 & drug interactions
- 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, including phenytoin.(34221552, 33999428)
- 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.
- Mechanism of action: Selectively enhances voltage-dependent sodium channel slow inactivation, thereby inhibiting neuronal firing.(34221552)
- Half-life is generally 13 hours.
- 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 antiseizure 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.
dosing & advantages 💊
status epilepticus
- 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.
- Maintenance: 1-3 mg/kg/day given daily or divided q12hr (e.g., 50-100 mg IV q12hr).(33896531; 34300194, 34798964)
- Trough levels may be monitored to ensure appropriate dosing (more on this below).
- Advantages: Phenobarbital isn't typically a front-line antiseizure medication. However, phenobarbital is effective and perhaps underutilized:
adjunctive sedative agent
- Loading dose:
- Typically, 10-15 mg/kg.
- May be provided as a single dose among intubated, hemodynamically stable patients (although usually no more than 10 mg/kg).
- May be provided in multiple divided doses, if there are concerns regarding hypotension or oversedation.
- Maintenance dose:
- 1-2 mg/kg PO or IV daily may be considered among patients on prolonged mechanical ventilation.
- For patients on shorter-term ventilation (e.g., <1 week), maintenance doses may not be needed.
- Therapeutic drug monitoring: For patients receiving maintenance doses of phenobarbital, occasionally measuring levels might enhance safety. The optimal level isn't well defined, but 15-25 ug/mL (64-107 uM/L) might be a reasonable target. More on phenobarbital levels below.
- Use of phenobarbital as a sedative:
- Phenobarbital is occasionally useful as an adjunctive sedative agent for intubated patients. It is especially useful for patients with alcoholism or very high propofol requirements. Phenobarbital may act synergistically with propofol, thereby allowing lower propofol doses to be utilized (reducing the risk of propofol infusion syndrome).
- Occasionally, phenobarbital may be useful to provide basal sedation in a non-intubated and very difficult-to-sedate patient.
- ⚠️ Be careful: Phenobarbital has a long half-life. If the patient is alternating between hyperactive and hypoactive delirium, phenobarbital could promote excessive sedation that could be long-lasting.
alcohol withdrawal
monitoring phenobarbital level
interpretation of phenobarbital trough levels
- Therapeutic range for epilepsy: 15-40 ug/mL (64-172 uM).
- However, some authors recommend targeting 20-50 mg/L.(34798964)
- Mild toxicity (e.g., ataxia, nystagmus): >50 ug/mL (>215 uM).
- Severe toxicity can occur (e.g., stupor/coma): >65 ug/mL (>280 uM)
predicting phenobarbital level based on loading dose
Level = 1.5[Dose in mg/kg]
- 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).
- Phenobarbital has a very long half-life. Thus, if several doses are administered over a short time frame (e.g., <24 hours), the phenobarbital level may be estimated with reasonable accuracy.
when should levels be checked?
- Multiple doses of phenobarbital over time: The half-life of phenobarbital is variable, so the steady-state phenobarbital level may be unpredictable.
- Morbid obesity:
- One study suggests that the phenobarbital may be dosed based on the patient's actual body weight.(1587059) However, this isn't well validated.
- A reasonable approach may be to provide an initial dose based on an adjusted body weight, followed by a phenobarbital level after 2 hours. A single level will be sufficient to calculate the volume of distribution (so levels may only be needed intermittently).
- Alcohol withdrawal: Checking levels is usually unnecessary, as long as the cumulative dose of phenobarbital is maintained below 20 mg/kg. However, if the dosing history is unclear then a phenobarbital level can be helpful.
contraindications and drug interactions
contraindications & cautions:
- Pregnancy.
- Advanced cirrhosis: Patients with borderline hepatic encephalopathy are at high risk of oversedation. Phenobarbital should generally be avoided in any patient with a history of hepatic encephalopathy. If phenobarbital is utilized in a patient with hepatic dysfunction, it should be dose-reduced.
- Drug interaction with an essential medication that isn't easily dose-adjusted (more on this below).
- Acute intermittent porphyria.
- Prior chronic phenobarbital use, or prior phenobarbital loading: This isn't a contraindication to using phenobarbital, but be careful about giving a loading dose to someone who already has a therapeutic level.
- Patient has received sedating medications (especially benzodiazepine): Phenobarbital will function synergistically with benzodiazepines, which could promote excessive sedation. This isn't an absolute contraindication; phenobarbital may often be used safely by giving smaller, divided doses.
- Multiple active neurological problems. This is a relative contraindication. For patients with fluctuating levels of consciousness, there is an increased risk that phenobarbital could lead to over-sedation (when combined with a deterioration in the underlying neurologic status).
drug interactions
- Phenobarbital is an inducer of CYP 2B6, 2C9, and 3A4, which may lead to inadequate levels of medications metabolized by these pathways.(33176370) It may be necessary to adjust the dose of other medications that the patient is on (e.g., phenytoin and valproate). However, CYP enzyme induction may be less problematic if only phenobarbital loading is utilized, without ongoing chronic therapy.(32794143)
- Notable medications metabolized by these enzymes include the following:
- Antivirals (e.g., efavirenz, nevirapine, ritonavir, velpatasvir)
- Antidepressants (amitriptyline, bupropion, buspirone, citalopram, escitalopram, fluoxetine, venlafaxine).
- Antipsychotics (aripiprazole, haloperidol, quetiapine, risperidone, ziprasidone).
- Azole antifungals (voriconazole, isavuconazole).
- Gastrointestinal (proton pump inhibitors, ondansetron).
- Immunosuppressive (cyclosporine, dexamethasone, hydrocortisone, sirolimus, ruxolitinib, tacrolimus, tofacitinib).
- Neurologics (carbamazepine, clobazam, doxepin, methadone, phenytoin, selegiline, trazodone, valproic acid).
- Cardiovascular (amlodipine, apixaban, cilostazol, clopidogrel, diltiazem, eplerenone, irbesartan, ivabradine, lidocaine, losartan, nifedipine, nimodopine, rivaroxaban, torsemide, ticagrelor, warfarin).
- Oncologics (e.g., capecitabine, crizotinib, cyclophosphamide, sorafenib, tamoxifen).
- Phenobarbital is metabolized by CYP2C9 and 2C19, which may lead to drug-drug interactions. For example:
- 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)
- When in doubt, check for interactions using the Medscape Drug Interaction Checker. 🌊
side effects
- 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.
pharmacology and mechanism of action
- Mechanism of action:
- Stimulates inhibitory GABA-A receptors.
- Inhibits AMPA-type glutamate receptors.
- Phenobarbital may be administered via IV, IM, or PO routes (all with ~100% bioavailability).
- Phenobarbital is mostly metabolized in the liver (CYP2C9 > 2C19), but ~25% may be excreted unchanged in urine.(30921021)
- The half life is typically ~80 hours, but may vary from ~50-140 hours.(Torbey, 2019)
dosing 💊
dosing for status epilepticus
- 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)
dosing: sedative infusion for intubated patient
- Long-term use of high doses may cause propofol infusion syndrome. This may be avoided by:
- (1) Using doses <<83 mcg/kg/min (<<5 mg/kg/hr).
- (2) Providing enteral nutrition.
- (3) Following triglyceride levels q48hr (discussed further below).
- Maintenance propofol infusions are ideally run at ~0-50 mcg/kg/min (0-3 mg/kg/hr). Using higher doses increases the likelihood that propofol will increase the triglyceride level and need to be discontinued entirely.
contraindications & adverse events
- Hypotension is a relative contraindication.
- This can generally be managed by combining propofol with a low-dose vasopressor infusion (e.g., phenylephrine or norepinephrine), to counterbalance vasodilation due to the propofol.
- Hypertriglyceridemia.
- Triglyceride levels should be monitored q48hr.
- If triglyceride levels are gradually creeping up, try reducing the propofol dose.
- If the triglyceride level is >500-800 mg/dL, propofol probably needs to be stopped.(32844730) However, some institutions have recently started tolerating triglyceride levels up to 1,000 mg/dL before stopping propofol.(33068459)
- Propofol infusion syndrome.
- Pancreatitis.
- Bradycardia may occur occasionally.
- (Egg allergy is not a contraindication.)
- (Green urine due to propofol does not correlate with propofol infusion syndrome. This is not an indication to stop the propofol.)
indications & advantages
propofol for status epilepticus:
- Preferred agent, easy to titrate.
- If abruptly stopped, patients may have rebound seizure.
propofol for sedation:
- Propofol is a front-line sedative agent (alongside dexmedetomidine).
- Benefits of propofol:
- Rapid onset and offset, facilitating neurologic evaluation and extubation.
- Antiepileptic properties.
- Neuroprotective properties (including reduction of intracranial pressure).
- Does not seem to elicit tolerance or withdrawal. This may be useful among patients who require long-term intubation.
- Suppresses respiration (which can be helpful among ventilated patients to reduce ventilator dyssynchrony).
pharmacology, mechanism of action
- Mechanism of action: (34300194, 33480193)
- Stimulates inhibitory GABA receptors
- Inhibits NMDA receptors
- May reduce calcium influx through slow calcium channels.
- A more broad-based mechanism of action might explain why propofol retains potency over time for seizures, whereas midazolam (which solely works via GABA receptors) becomes less effective over time.
- Triglyceride levels should be monitored q48hr.
dosing 💊
dosing for status epilepticus
- 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)
dosing: pain-dose ketamine infusions
- The typical dosing range is 0.1-0.3 mg/kg ketamine per hour (e.g., ~8-20 mg/hour). However, guidelines suggest that doses up to 1 mg/kg/hour may be used, with close monitoring for psychomimetic side effects.(29870457) 📄
- For most patients, it's useful to start at the lower end of this dosing range, and then up-titrate the ketamine gradually over a period of hours as needed. Around ~0.25mg/kg/hr ketamine often starts to cause psychomimetic side effects (which may vary, spanning the gamut of somnolence, agitation, euphoria, or hallucinations). These effects are usually not problematic (e.g., mild sedation or euphoria). However, some patients may experience disturbing hallucinations. If troublesome psychomimetic side effects occur, then pause the ketamine infusion for an hour or two and resume at a lower dose (a dose which didn't cause psychomimetic side effects). Resuming ketamine at a lower dose can often still allow the patient to receive substantial benefit from ketamine, without experiencing any side effects.
- If you're very worried about psychomimetic side effects, you could just leave the infusion at a fixed rate of 0.12 mg/kg/hour. Several studies suggest that the risk of psychomimetic effects at that dose is close to zero. (25530168, 15983467, 21676160) This strategy might be reasonable in an intubated patient with baseline agitation, where it may be difficult to determine whether the patient is experiencing psychomimetic side effects.
dosing: intermittent ketamine boluses for pain
- Ketamine may be utilized for analgesia as intermittent doses given as needed (at a dose of ~0.1-0.3 mg/kg, administered intravenously over 5-15 minutes). When using a dose of 0.3 mg/kg, gradual infusion over 15 minutes reduces the incidence of psychomimetic side effects.(28283340)
- A test dose may be used to assess how the patient responds to ketamine. If there is a favorable response, this could support the rationale for setting up a pain-dose ketamine infusion.
dosing: complete dissociative analgosedation
- Ketamine is infused at a rate of 1-5 mg/kg/hour.
- The goal is complete dissociation.
contraindications & side effects
contraindications
- Dangerously uncontrolled hypertension (may be exacerbated by ketamine).
- Pregnancy (based on developmental delays in animal studies).(29870457)
- Severe hepatic dysfunction.
- Active psychosis or delirium is a relative contraindication to using doses above 0.1 mg/kg/hour (because it may be difficult to determine if the patient is suffering from psychomimetic side-effects due to the ketamine).
side effects / problems
- Hypertension.
- Hypersalivation, increased bronchial secretions (which may be especially problematic with a BiPAP mask interface).
- Psychomimetic effects (although usually not very harmful, there is a risk of causing disturbing hallucinations).
- Ketamine has erratic effects on Bispectral index (BIS) monitoring, rendering this form of monitoring less.
indications & advantages
general advantages of ketamine
- Hemodynamic stability (may cause a mild increase in blood pressure at higher doses).
- Does not suppress respiration (allowing ketamine to be used among intubated or nonintubated patients).
- Causes bronchodilation.
- Exerts an antiseizure effect.
- Antidepressant effects could potentially mitigate post-ICU depressive symptoms.
- Ketamine may help prevent the development of tolerance to opioids and possibly to dexmedetomidine.
use of ketamine in status epilepticus
- 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)
use of ketamine for pain
- Pain-dose ketamine infusions provide a mild to moderate level of analgesia (with some variation between patients). This often isn't sufficient to control the pain entirely, but it may provide a continuous basal level of analgesia with opioid-sparing effects. (25530168) Increasing evidence supports the use of pain-dose ketamine infusions among critically ill patients. (12933413, 26025196, 28468568)
- Pain-dose ketamine is extraordinarily safe (e.g., there is no risk of respiratory suppression or hypotension).
- Ketamine may inhibit the development of tolerance to opioids and the emergence of opioid induced hyperalgesia. (15983467, 16854557, 23269131, 14581110) Thus, ketamine may mitigate some side effects of opioids.
- Ketamine exerts antidepressant effects, which may improve patient mood and promote participation in rehabilitation. (26025196, 23428794, 16894061)
- One randomized controlled trial found that pain-dose ketamine infusions reduced the risk of delirium. (30268528). This suggests that the possibility of psychomimetic side effects doesn't imply a danger of more serious neurologic complications from ketamine.
use of ketamine for complete dissociative analgosedation
- Complete dissociation with a high-dose ketamine infusion may rarely be used for intubated patients, to provide both sedation and analgesia. This is useful in the following situations:
- (1) Agitation refractory to other agents.
- (2) Severe hypotension prevents the use of other treatments (e.g., propofol or dexmedetomidine).
- (3) Status asthmaticus.
- High-dose ketamine is a one-drug solution that treats both agitation and analgesia. One of the benefits of dissociative ketamine is that other sedatives and analgesics (e.g., opioids) can be stopped. This will avoid tolerance and subsequent withdrawal symptoms.
pharmacology, mechanism of action
- Ketamine functions as an NMDA-receptor antagonist.
- At very low doses, ketamine provides analgesia without other neurologic effects.
- At higher doses, ketamine has anti-seizure effects and dissociative effects.
- Half-life of 2-3 hours.(33480193)
- Hepatic metabolism, with no dose adjustment in renal failure. Consider dose reduction in hepatic impairment.(33896531)
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 & drug interactions
- 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).
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 & drug interactions
- Hemodynamic instability
- Porphyria
- Pentobarbital has numerous drug-drug interactions.
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.
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 & drug interactions
- 🛑 Coadministration with valproic acid may increase the risk of hyperammonemia (topiramate inhibits glutamine synthetase, leading to reduced ammonia metabolism).(33176370)
- Pregnancy.
- Nephrolithiasis.
side effects
- Renal tubular acidosis (inhibits carbonic anhydrase, causing renal bicarbonate loss).
- Drowsiness.
indications & advantages
- 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).
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 & drug interactions
- 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)
- Perampanel accelerates metabolism of levonorgestrel, a component of some oral contraceptives.
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).
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 bioavailability.
- 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.
dosing 💊
- Loading dose of 20-40 mg.(36333031)
- Maintenance dose of 10-40 mg/day in two divided oral doses.
contraindications & drug interactions
- Severe hepatic dysfunction.
- Caution in renal dysfunction (GFR < 30 ml/min).(36333031)
- 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.
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.
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)
- 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.
Follow us on iTunes
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
- = Link to online calculator.
- = Link to Medscape monograph about a drug.
- = Link to IBCC section about a drug.
- = Link to IBCC section covering that topic.
- = Link to FOAMed site with related information.
References
- 09738086 Treiman DM, Meyers PD, Walton NY, Collins JF, Colling C, Rowan AJ, Handforth A, Faught E, Calabrese VP, Uthman BM, Ramsay RE, Mamdani MB. A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group. N Engl J Med. 1998 Sep 17;339(12):792-8. doi: 10.1056/NEJM199809173391202 [PubMed] 📄
- 20878265 Rossetti AO, Milligan TA, Vulliémoz S, Michaelides C, Bertschi M, Lee JW. A randomized trial for the treatment of refractory status epilepticus. Neurocrit Care. 2011 Feb;14(1):4-10. doi: 10.1007/s12028-010-9445-z [PubMed]
- 21967361 Silbergleit R, Lowenstein D, Durkalski V, Conwit R; Neurological Emergency Treatment Trials (NETT) Investigators. RAMPART (Rapid Anticonvulsant Medication Prior to Arrival Trial): a double-blind randomized clinical trial of the efficacy of intramuscular midazolam versus intravenous lorazepam in the prehospital treatment of status epilepticus by paramedics. Epilepsia. 2011 Oct;52 Suppl 8(Suppl 8):45-7. doi: 10.1111/j.1528-1167.2011.03235.x [PubMed]
- 22335736 Silbergleit R, Durkalski V, Lowenstein D, Conwit R, Pancioli A, Palesch Y, Barsan W; NETT Investigators. Intramuscular versus intravenous therapy for prehospital status epilepticus. N Engl J Med. 2012 Feb 16;366(7):591-600. doi: 10.1056/NEJMoa1107494 [PubMed]
- 24453083 Thakur KT, Probasco JC, Hocker SE, Roehl K, Henry B, Kossoff EH, Kaplan PW, Geocadin RG, Hartman AL, Venkatesan A, Cervenka MC. Ketogenic diet for adults in super-refractory status epilepticus. Neurology. 2014 Feb 25;82(8):665-70. doi: 10.1212/WNL.0000000000000151 [PubMed]
- 28833346 Gagnon DJ, Fontaine GV, Riker RR, Fraser GL. Repurposing Valproate, Enteral Clonidine, and Phenobarbital for Comfort in Adult ICU Patients: A Literature Review with Practical Considerations. Pharmacotherapy. 2017 Oct;37(10):1309-1321. doi: 10.1002/phar.2017 [PubMed]
- 29666958 Osman GM, Araújo DF, Maciel CB. Ictal Interictal Continuum Patterns. Curr Treat Options Neurol. 2018 Apr 18;20(5):15. doi: 10.1007/s11940-018-0500-y [PubMed]
- 30516601 Nelson SE, Varelas PN. Status Epilepticus, Refractory Status Epilepticus, and Super-refractory Status Epilepticus. Continuum (Minneap Minn). 2018 Dec;24(6):1683-1707. doi: 10.1212/CON.0000000000000668 [PubMed]
- LaRoche, S. M., & Haider, H. A. (2018). Handbook of ICU EEG Monitoring (2nd ed.). Demos Medical.
- 30638692 Park EG, Lee J, Lee J. The ketogenic diet for super-refractory status epilepticus patients in intensive care units. Brain Dev. 2019 May;41(5):420-427. doi: 10.1016/j.braindev.2018.12.007 [PubMed]
- 30921018 VanHaerents S, Gerard EE. Epilepsy Emergencies: Status Epilepticus, Acute Repetitive Seizures, and Autoimmune Encephalitis. Continuum (Minneap Minn). 2019 Apr;25(2):454-476. doi: 10.1212/CON.0000000000000716 [PubMed]
- 30921021 Abou-Khalil BW. Update on Antiepileptic Drugs 2019. Continuum (Minneap Minn). 2019 Apr;25(2):508-536. doi: 10.1212/CON.0000000000000715 [PubMed]
- 31766004 Minicucci F, Ferlisi M, Brigo F, Mecarelli O, Meletti S, Aguglia U, Michelucci R, Mastrangelo M, Specchio N, Sartori S, Tinuper P. Management of status epilepticus in adults. Position paper of the Italian League against Epilepsy. Epilepsy Behav. 2020 Jan;102:106675. doi: 10.1016/j.yebeh.2019.106675 [PubMed]
- 31774955 Kapur J, Elm J, Chamberlain JM, Barsan W, Cloyd J, Lowenstein D, Shinnar S, Conwit R, Meinzer C, Cock H, Fountain N, Connor JT, Silbergleit R; NETT and PECARN Investigators. Randomized Trial of Three Anticonvulsant Medications for Status Epilepticus. N Engl J Med. 2019 Nov 28;381(22):2103-2113. doi: 10.1056/NEJMoa1905795 [PubMed]
- 32049893 Barra ME, Phillips KM, Chung DY, Rosenthal ES. A Novel Correction Equation Avoids High-Magnitude Errors in Interpreting Therapeutic Drug Monitoring of Phenytoin Among Critically Ill Patients. Ther Drug Monit. 2020 Aug;42(4):617-625. doi: 10.1097/FTD.0000000000000739 [PubMed]
- Torbey, M. T. (2019). Neurocritical Care (2nd ed.). Cambridge University Press.
- Shutter, L. A., Molyneaux, B. J. (2019). Neurocritical care. Oxford University press.
- Wijdicks E.F.M., Findlay, J. Y., Freeman, W. D., Sen A. (2019). Mayo Clinic critical and Neurocritical Care Board Review. Oxford University Press.
- 33176370 Der-Nigoghossian C, Tesoro EP, Strein M, Brophy GM. Principles of Pharmacotherapy of Seizures and Status Epilepticus. Semin Neurol. 2020 Dec;40(6):681-695. doi: 10.1055/s-0040-1718721 [PubMed]
- 33273175 Lee EQ. Neurologic Complications in Patients With Cancer. Continuum (Minneap Minn). 2020 Dec;26(6):1629-1645. doi: 10.1212/CON.0000000000000937 [PubMed]
- Nelson, S. E., & Nyquist, P. A. (2020). Neurointensive Care Unit: Clinical Practice and Organization (Current Clinical Neurology) (1st ed. 2020 ed.). Springer.
- 33480193 Kim D, Kim JM, Cho YW, Yang KI, Kim DW, Lee ST, No YJ, Seo JG, Byun JI, Kang KW, Kim KT; Drug Committee of Korean Epilepsy Society. Antiepileptic Drug Therapy for Status Epilepticus. J Clin Neurol. 2021 Jan;17(1):11-19. doi: 10.3988/jcn.2021.17.1.11 [PubMed]
- 33664203 Rossetti AO, Alvarez V. Update on the management of status epilepticus. Curr Opin Neurol. 2021 Apr 1;34(2):172-181. doi: 10.1097/WCO.0000000000000899 [PubMed]
- 33896531 Ameli PA, Ammar AA, Owusu KA, Maciel CB. Evaluation and Management of Seizures and Status Epilepticus. Neurol Clin. 2021 May;39(2):513-544. doi: 10.1016/j.ncl.2021.01.009 [PubMed]
- 34221552 Kirmani BF, Au K, Ayari L, John M, Shetty P, Delorenzo RJ. Super-Refractory Status Epilepticus: Prognosis and Recent Advances in Management. Aging Dis. 2021 Jul 1;12(4):1097-1119. doi: 10.14336/AD.2021.0302 [PubMed]
- 34300194 Alolayan YS, McKinley K, Bhatia R, Alkhachroum A. Review and Updates on the Treatment of Refractory and Super Refractory Status Epilepticus. J Clin Med. 2021 Jul 7;10(14):3028. doi: 10.3390/jcm10143028 [PubMed]
- 34618762 Rosenthal ES. Seizures, Status Epilepticus, and Continuous EEG in the Intensive Care Unit. Continuum (Minneap Minn). 2021 Oct 1;27(5):1321-1343. doi: 10.1212/CON.0000000000001012 [PubMed]
- 34619776 Al-Faraj AO, Abdennadher M, Pang TD. Diagnosis and Management of Status Epilepticus. Semin Neurol. 2021 Oct;41(5):483-492. doi: 10.1055/s-0041-1733787 [PubMed]
- 34697528 Boggs JG. Seizure Management in the Intensive Care Unit. Curr Treat Options Neurol. 2021;23(11):36. doi: 10.1007/s11940-021-00692-2 [PubMed]
- LaHue S.C. and Levin M. (2021). Emergency Neurology (What Do I Do Now) (2nd ed.). Oxford University Press.
- Louis ED, Mayer SA, Noble JM. (2021). Merritt’s Neurology (Fourteenth). LWW.
- 34798964 Fan JM, Singhal NS, Guterman EL. Management of Status Epilepticus and Indications for Inpatient Electroencephalography Monitoring. Neurol Clin. 2022 Feb;40(1):1-16. doi: 10.1016/j.ncl.2021.08.001 [PubMed]
- 35001380 Migdady I, Rosenthal ES, Cock HR. Management of status epilepticus: a narrative review. Anaesthesia. 2022 Jan;77 Suppl 1:78-91. doi: 10.1111/anae.15606 [PubMed]
- 35131079 Walker A, Rupal A, Jani C, Al Omari O, Singh H, Patel D, Perrino C, McCannon J. Longstanding Phenytoin Use as a Cause of Progressive Dyspnea. Chest. 2022 Feb;161(2):e91-e96. doi: 10.1016/j.chest.2021.08.079 [PubMed]
- 35393968 Abou-Khalil BW. Update on Antiseizure Medications 2022. Continuum (Minneap Minn). 2022 Apr 1;28(2):500-535. doi: 10.1212/CON.0000000000001104 [PubMed]
- 35393970 Trinka E, Leitinger M. Management of Status Epilepticus, Refractory Status Epilepticus, and Super-refractory Status Epilepticus. Continuum (Minneap Minn). 2022 Apr 1;28(2):559-602. doi: 10.1212/CON.0000000000001103 [PubMed]
- 35449037 Bilbao-Meseguer I, Barrasa H, Rodríguez-Gascón A, Asín-Prieto E, Maynar J, Sánchez-Izquierdo JÁ, Solinís MÁ, Isla A. Optimization of levetiracetam dosing regimen in critically ill patients with augmented renal clearance: a Monte Carlo simulation study. J Intensive Care. 2022 Apr 21;10(1):21. doi: 10.1186/s40560-022-00611-w [PubMed]
- 35605086 Heuser K, Olsen KB, Ulvin LB, Gjerstad L, Taubøll E. Modern Treatment of Status Epilepticus in Adults. In: Czuczwar SJ, editor. Epilepsy [Internet]. Brisbane (AU): Exon Publications; 2022 Apr 2. Chapter 5 [PubMed]
- Albin, C. S. W., & Zafar, S. F. (2022). The Acute Neurology Survival Guide: A Practical Resource for Inpatient and ICU Neurology (1st ed. 2022 ed.). Springer.
- 36333031 Ammar A, Ammar MA, Tesoro EP. Neuropharmacology in the Intensive Care Unit. Crit Care Clin. 2023 Jan;39(1):171-213. doi: 10.1016/j.ccc.2022.07.007 [PubMed]
- 36333039 Coppler PJ, Elmer J. Status Epilepticus: A Neurologic Emergency. Crit Care Clin. 2023 Jan;39(1):87-102. doi: 10.1016/j.ccc.2022.07.006 [PubMed]