It seems that our IV secondary antiepileptics are as good as a coin flip for seizure termination. Let's talk seven; four "proven" and three additional options -
The 2016 American Epilepsy Society Guidelines recommends intravenous (IV) lorazepam and intramuscular (IM) midazolam) as first-line therapy. Underdosed benzodiazepines are a whole discussion for another day. As new anticonvulsants become available, IV administration has been investigated.
The ESETT trial showed that levetiracetem, fosphenytoin, and valproic acid have a similiar safety profile and seizure termination efficacy. Vimpat (lacosamide) and Briviact (brivaracetem) are fairly new to most. Patients with complex epilepy past medical histories may need different mechanisms to terminate seizures. Here are 7 IV secondary antiepileptics for status epilepticus. (no particular order)
Antiepileptic Drug (AED) #1 - Levetiracetem
Mechanism of action
Inhibits Synaptic Vesicle Protein 2A, decreasing vesicular priming and neurotransmission
Dosing
60 mg/kg IV (max 4500 mg)
Adverse Drug Reactions (>5% compared to placebo)
Somnolence
Asthenia
Infection
Dizziness
Warnings and Precautions
Psychiatric reactions
Somnolence, fatigue
Dermatologic reactions
Withdrawal seizures
Insight
Without concerns for hepatic impairment/drug-drug interactions, levetiracetem can be given in most patients. May be given IV push. Note vials are 100 mg/mL, 5 mLs each.
AED #2 - Fosphenytoin
Mechanism of action
Modulation of voltage-dependent Na/Ca2+ channels of neurons
Inhibition of Ca flux across neuronal membranes
Dosing
20 mg/kg phenytoin equivalents (PE) IV (max 1500 mg)
Adverse Drug Reactions
Nystagmus
Dizziness
Hypotension
Pruritis
Warnings and Precautions
Withdrawal seizures
Cardiovascular depression
Rash
Hepatic injury
Hematologic disorders
Fetal risk
Contraindicated
Phenytoin/fosphenytoin component hypersensitivity
Sinus bradycardia, sino-atrial block, second and third degree A-V block, and Adams-Stokes syndrome
Insight
Phenytoin is a class IB antiarrythmic. The medication has several concerning adverse effects associated with it, especially with rapid IV fosphenytoin infusions. Not my preferred initial agent. Tend to only reach if patient is on it and suspicious for non-adherence.
AED #3 - Valproic acid
Mechanism of action
Modulation of voltage-dependent Na/Ca2+ channels of neurons
Promotes elevations of GABA brain concentrations
Dosing
40 mg/kg IV (max 3000 mg)
Adverse Drug Reactions(>5%): abdominal pain, alopecia, amblyopia/blurred vision, amnesia, anorexia, asthenia, ataxia, bronchitis, constipation, depression, diarrhea, diplopia, dizziness, dyspepsia, dyspnea, ecchymosis, emotional lability, fever, flu syndrome, headache, increased appetite, infection, insomnia, nausea, nervousness,
nystagmus, peripheral edema, pharyngitis, rhinitis, somnolence, thinking abnormal, thrombocytopenia, tinnitus, tremor, vomiting, weight gain, weight loss (straight from the packaage insert)
Warnings and Precautions
Withdrawal seizures
Hepatotoxicity
Pancreatitis
Fetal risk
Mood disturbances
Hematologic disorders
Hyperammonemia
Severe skin reactions
Contraindicated
Hepatic dysfunction
Mitochondrial disorders
Suspected POLG-related disorder
Known hypersensitivity
Urea cycle disorders
Insight
Limited by adverse drug reactions. Commonly a part of patient home regimens for mood. May be preferred in patients with behavioral health history.
AED #4 - Lacosamide
Mechanism of action
Enhances slow inactivation of voltage-gated sodium channels, resulting in stabilization of hyperexcitable neuronal membranes and inhibition of repetitive neuronal firing
Dosing
200 - 600 mg IV push
Comes in 200 mg/20 mL vial
Adverse Drug Reactions(>10%)
Diplopia, headache, dizziness, nausea
Warnings and Precautions
Mood disturbances
Cardiac conduction abnormalities/history
Withdrawal seizure
Contraindicated
Known hypersensitivity
No other listed per package insert
Insight
Lacosamide does show promise for status epilepticus, but needs more solid evidence. It is unfortuanate that the ESETT trial didn't include lacosamide. Off-label use of lacosamide for status epilepticus puts termination rates around 50%. Prolonged PR intervals warrants concern in those with a cardiac history,.
Mechanism of action
Antagonism of N-methyl-D-aspartate in central nervous system
Dosing
1 - 4 mg/kg IV push
Adverse Drug Reactions
Associated with hypertension and tachycardia, may cause bradycardia and hypotension
Emergence reactions (>12%) - treat with benzodiazepines
Hypersalivation
Nausea/vomiting
Tonic movements
Warnings and Precautions
Cardiovascular instability
May induce apnea and laryngeal-spasm
Intraocular pressures
Contraindicated
Known hypersensitivity
Insight
The use specifically in status epilepticus on as secondary IV anticonvulsant is not common. More evidence supports use in refractory and super refractory status epilepticus, in addition to a continuous infusion. Glutamate reduction may be beneficial as an adjunct therapy in certain patients.
AED #6 - Briviact (brivaracetem)
Mechanism of action
Inhibits Synaptic Vesicle Protein 2A, decreasing vesicular priming and neurotransmission
Dosing
200 mg (50 - 400 mg) IV over 15 minutes
Adverse Drug Reactions(>5%)
Somnolence/sedation, dizziness, fatigue, and nausea/vomiting
Warnings and Precautions
Suicidal bevhavior
Psychiatric disturbance
Hypersensitivity, including bronchospasm and angioedema
Withdrawal seizure
Contraindicated
Known hypersensitivity
Insight
Recently introduced to the market in 2016. Brivaracetem is should theoretically be levetiracetem with a higher affinity for the same receptor. There has been increased chronic use in patients. With more evidence in the future, brivaracetem may have an indication for status epilepticus.
AED #7 - Phenobarbital
Mechanism of action
Prolongs opening of Cl- channels (enhances GABA)
Antagonism of NMDA receptor
Dosing
15 mg/kg IV push
Adverse Drug Reactions: Dizziness, headache, "hangover" confusion especially in the elderly, paradoxical excitation, exacerbation of pre-existing pain, nausea, vomiting, epigastric pain, hypotension, facial edema, skin rash with bullae and vesicles, purpura, erythema multiforme, exfoliative dermatitis (rare), megaloblastic anemia, agranulocytosis and thrombocytopenia.
Warnings and Precautions
Drug-drug interactions
Contraindicated
Known hypersensitivity
Porphyria
New borns
Insight
Go-To: Alcohol withdrawal seizures and delirium tremens (DTs).
Maximize BZDs at Guideline-Recommended Doses Before Secondary Anticonvulsants
Status epilepticus is associated with significant morbidity and mortality. Benzodiazepines are first line therapy. We have several secondary IV AEDs, but it appears that they're as good as a coin flip for seizure termination. Keep these 7 agents in mind; levetiracetem, fosphenytoin, valproic acid, lacosamide, ketamine, brivaracetem, and phenobarbital. Rather than finding the best secondary agent, I cannot emphasize enough how important it is to maximize benzodiazepines at guideline-recommended doses.
Mark Nguyen, PharmD, BCEMP
References
Contreras-Garcia et al. Levetiracetam Mechanisms of Action: From Molecules to Systems. Pharmaceuticals (Basel). 2022 Apr 13;15(4):475. doi: 10.3390/ph15040475.
Santamarina et al. Intravenous lacosamide (LCM) in status epilepticus (SE): Weight-adjusted dose and efficacyEpilepsy Behav. 2018 Jul;84:93-98. doi: 10.1016/j.yebeh.2018.04.025
Hofler J, Trinka E. Intravenous ketamine in status epilepticus. Epilepsy Beha. 2018 Jul;84:93-98. doi: 10.1016/j.yebeh.2018.04.025.
Aicua-Rapun et al. Intravenous brivaracetam in status epilepticus: Correlation between loading dose, plasma levels and clinical response. Epilepsy Behav. 2018 Jul;84:93-98. doi: 10.1016/j.yebeh.2018.04.025.
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