3.2 Anti-Seizure Drugs

Seizure pharmacology in the neuro ICU is a dosing and toxicity problem, not a brand-preference problem. This section covers intravenous loads, maintenance, organ-specific cautions, and how Established Status Epilepticus Treatment Trial (ESETT) 2019 informs the second-agent choice. The full status epilepticus algorithm—timing definitions, benzodiazepine first-line details, and EEG titration—belongs in the seizures chapter. You still must know the loads here, because wrong milligrams, wrong infusion rates, and ignored interactions appear as standalone pharmacology items.

Load versus maintenance

A load is a mg/kg intravenous dose meant to produce a therapeutic brain concentration within minutes. Maintenance starts after the load, usually divided twice or three times daily, and is adjusted for kidneys, liver, interactions, and levels. Giving only a maintenance tablet to a convulsing patient is not treatment. Giving a huge load and then forgetting maintenance lets levels collapse overnight.

For benzodiazepine-refractory convulsive status epilepticus, ESETT randomized children and adults to levetiracetam ~60 mg/kg (maximum 4500 mg), fosphenytoin 20 mg phenytoin equivalents (PE)/kg, or valproate 40 mg/kg. Seizure cessation and safety were similar (roughly 45–47% success in the primary analysis). That is pharmacologic equivalence among those three second agents—not a reason to skip the benzodiazepine, and not proof that lacosamide, brivaracetam, or phenobarbital are identical.

Levetiracetam

Levetiracetam binds synaptic vesicle protein 2A (SV2A). It is renally cleared, has few cytochrome interactions, and is available intravenous and oral at 1:1. The ESETT load is 60 mg/kg IV, maximum 4500 mg, typically over about 10 minutes. Maintenance after a load is often in the range of 1000–1500 mg twice daily, or about 30–40 mg/kg/day, reduced in kidney injury. Adverse effects include somnolence, irritability, and psychiatric symptoms. Those behavioral effects matter in a recovering ICU patient but rarely decide the emergency load.

Fosphenytoin and phenytoin

Phenytoin blocks voltage-gated sodium channels and follows saturable (Michaelis–Menten) kinetics: small dose increases can produce large level jumps once enzymes are saturated. Total levels of about 10–20 mcg/mL are the usual target; check a free phenytoin level when albumin is low, when the patient has renal failure, or when valproate is co-administered, because valproate displaces phenytoin from protein.

Intravenous phenytoin is dissolved in propylene glycol and is caustic. Maximum infusion rate is 50 mg/min in adults (slower in elderly or cardiac disease). Rapid infusion causes hypotension and bradyarrhythmias; monitor the electrocardiogram and blood pressure. Purple glove syndrome—distal edema, purple discoloration, and pain—follows peripheral phenytoin extravasation or even some uneventful peripheral infusions.

Fosphenytoin is a water-soluble prodrug dosed in PE. The status load is 20 mg PE/kg IV. Maximum infusion rate is 150 mg PE/min, which is why fosphenytoin is preferred over phenytoin when a fast sodium-channel load is chosen. Cardiac monitoring is still required. Fosphenytoin can cause pruritus, especially in the groin, from a phosphate load; that is not allergy. Hypotension still occurs, especially at high rates.

Phenytoin is a strong enzyme inducer (including CYP3A4). It can lower levels of nimodipine, midazolam, corticosteroids, and many other ICU drugs. Enteral phenytoin binds to tube feeds. Hold feeds about 1–2 hours before and after each enteral dose, or use the intravenous route. If feeds continue over phenytoin, levels fall and seizures return. This interaction is a classic exam trap in a patient who was loading well on day 1 and seizing on day 3 after a nasogastric feeding protocol started.

Valproate

Valproate (valproic acid) has sodium-channel, GABA, and histone-deacetylase effects. The ESETT load is 40 mg/kg IV (ESETT capped at 3000 mg) over about 5–10 minutes. Maintenance is often 10–15 mg/kg/day in divided doses, titrated to levels (typical total 50–100 mcg/mL) and to the EEG.

Serious toxicities you must recite: hepatotoxicity, including fulminant failure; hyperammonemia (with or without a high valproate level), worse with topiramate; pancreatitis; tremor; and thrombocytopenia plus platelet dysfunction. Hyperammonemic encephalopathy can look like worsening status or metabolic coma—check ammonia when mental status is worse than the EEG suggests.

Avoid valproate in mitochondrial disease, especially POLG mutations, because of liver failure. Avoid it as ongoing therapy in pregnancy because of neural-tube defects and neurodevelopmental harm. In life-threatening status, clinicians may still use an intravenous load when it is the best available second agent, then transition away. In a young woman with idiopathic generalized epilepsy who is not seizing, valproate is the wrong maintenance plan. Valproate also inhibits drug metabolism and can raise phenytoin free fraction—another reason to follow free levels when the two are combined. In active intracranial hemorrhage, thrombocytopenia and platelet dysfunction make valproate unattractive.

Lacosamide, brivaracetam, and phenobarbital

Lacosamide enhances slow inactivation of sodium channels. Intravenous loads of 200–400 mg (often 300–400 mg in status protocols) are given at a maximum of about 50 mg/min. The signature cardiac effect is PR-interval prolongation. Use caution in known atrioventricular block, sodium-channel blocker overdose, or combined with other PR-prolonging drugs. Lacosamide was not an ESETT arm; it is a reasonable adjunct, not a proven equivalent second-agent replacement for the ESETT trio.

Brivaracetam is a high-affinity SV2A ligand with intravenous and oral forms. Loads around 100–200 mg IV appear in status protocols. Psychiatric adverse effects may be fewer than with levetiracetam in some patients, but evidence for status superiority is not at ESETT scale. Dose-adjust in hepatic impairment.

Phenobarbital is a GABA-A agonist used as a second or third intravenous agent and as a bridge toward anesthetic coma. A typical load is 15–20 mg/kg IV at 50–100 mg/min with airway and blood-pressure support ready. Respiratory depression, hypotension, and prolonged sedation are expected. Levels are useful once the patient is no longer in convulsive crisis. Phenobarbital induces enzymes and interacts with many ICU medications.

Anesthetic infusions for refractory status epilepticus

When seizures continue after a benzodiazepine and an adequate second-agent load, the patient has refractory status epilepticus (RSE). Continuous infusions used to stop electroclinical seizures include midazolam, propofol, ketamine, and pentobarbital (or thiopental where available). These are titrated to EEG (often seizure suppression or burst suppression, depending on protocol and duration), not to a pretty bedside number alone.

Midazolam infusions tachyphylax and accumulate, especially with obesity, hepatic failure, and renal failure (active 1-hydroxymidazolam). Propofol is a potent anticonvulsant that lowers ICP and MAP; high dose plus long duration risks propofol infusion syndrome, taught in the next section. Ketamine is an NMDA antagonist that often supports blood pressure; control PaCO2 in ventilated patients if you are worried about cerebral blood flow. Pentobarbital is last-line for many teams: ileus, immunosuppression, myocardial depression, and days of lingering coma after you stop it.

Do not start a pentobarbital coma because the levetiracetam maintenance tablet was 500 mg twice daily in a 90 kg adult who never received a 60 mg/kg load. Underdosing the second agent is not RSE—it is incomplete treatment.

Practical comparison of common intravenous loads

Exam traps

Treating ESETT equivalence as permission to use a home-dose 500 mg levetiracetam vial as the entire load. Infusing phenytoin at fosphenytoin speed. Continuing tube feeds over enteral phenytoin. Giving valproate as maintenance to a pregnant patient or a known POLG mitochondrial syndrome. Ignoring PR prolongation with lacosamide in a patient with a new wide PR and a labile block. Calling the case RSE before the second agent was actually loaded. Combining high-dose propofol and high-dose midazolam without EEG and without a PRIS watch.

Maintenance pearls: after an ESETT-scale levetiracetam load, start a real maintenance dose that matches kidney function the same calendar day. After fosphenytoin, you are managing phenytoin—check a level at an appropriate post-distribution time, not 10 minutes after the infusion. After valproate, watch platelets, liver enzymes, and ammonia, especially if mental status diverges from the EEG.